CN104902898A - Diazole lactams - Google Patents

Diazole lactams Download PDF

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Publication number
CN104902898A
CN104902898A CN201380064138.1A CN201380064138A CN104902898A CN 104902898 A CN104902898 A CN 104902898A CN 201380064138 A CN201380064138 A CN 201380064138A CN 104902898 A CN104902898 A CN 104902898A
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alkyl
compound
ring
disease
mixture
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CN104902898B (en
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陈曦
樊平臣
李延东
J·P·鲍尔斯
V·马拉索恩
S·普那
田中裕子
张朋烈
D·德拉戈利
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Chemocentryx Inc
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    • A61K31/4164—1,3-Diazoles
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Abstract

Compounds are provided that act as potent antagonists of the CCR1 receptor, and have in vivo anti-inflammatory activity. The compounds are diazole lactam derivatives and are useful in pharmaceutical compositions, methods for the treatment of CCR1-mediated disease, and as controls in assays for the identification of competitive CCR1 antagonists.

Description

Diazole lactams
The cross reference of related application
To this application claims the series number submitted on June 6th, 2013 be series number that 61/831,700 and 2012 on December is submitted to for 7 is the priority of the U.S. Provisional Application of 61/734,705, and each application is incorporated herein by reference in their entirety.
About the statement of the right to the invention made under the research and development subsidized in federal government
Inapplicable.
Background of invention
The invention provides compound, comprise the pharmaceutical composition of one or more these compounds or their pharmaceutically acceptable salt, they effectively suppress various different chemotactic factor as the combination of MIP-1 α, leucotaxin (leukotactin), MPIF-1 and RANTES and CCR1 receptor.As antagonist or the regulator of CCR1 receptor, compound or compositions have effectiveness in treatment inflammatory and immunity disorder, symptom and disease.
Human health depends on human detection and destroys the ability of foreign pathogen, otherwise may consume precious resources from individuality and/or induce an illness.Immune system is the system of defense of human body, it comprises leukocyte (leukocyte (WBC): T and bone-marrow-derived lymphocyte, mononuclear cell, macrophage granulocyte, NK cell, mastocyte, dendritic cell, and derivative immunocyte (such as, osteoclast)), lymphoid tissue and lymph vessels.For opposing is infected, leukocyte circulates at body parts to detect pathogen.Once pathogen be detected, innate immune cell and cytotoxic T-Lymphocyte gather infection site thus eliminating pathogen especially.Chemotactic factor is used for raising and activating immune cell as molecular beacon, and as lymphocyte, mononuclear cell and granulocyte, determine pathogen location.
Although immune system has pathogen regulating action, certain inappropriate chemotactic factor signal transduction still can occur and think can trigger or maintain inflammatory diseases, as rheumatoid arthritis, and multiple sclerosis etc.Such as, in rheumatoid arthritis, chemotactic factor accumulation not modulated in osteoarthrosis causes and activates the macrophage and T cell that infiltrate.The activation of these cells causes synovial cell proliferation, causes inflammation and final bone and cartilage loss (see DeVries, M.E. etc., Semin Immunol 11 (2): 95-104 (1999)) at least partly.Some demyelination, feature as multiple sclerosis is that chemokine mediated monocyte/macrophage and T cell are raised to central nervous system (see Kennedy etc., J.Clin.Immunol.19 (5): 273-279 (1999)).The chemotactic factor of destructive WBC raises the follow-up rejection that graft participates in them.See DeVries, M.E. etc., the same.Because chemotactic factor plays pivotal role in inflammation and lymphocyte development, the ability of their activity of special manipulation has a significant impact the improvement and termination that are not satisfied with the disease of Therapeutic Method at present.In addition, graft rejection reaction can be reduced as far as possible, and without the need to the whole body of the immunosuppressive drug of costliness and complex effects.
Chemotactic factor be one group more than the little peptide (7-10kD) of 40 kinds, it combines the receptor of mainly expressing on WBC or immune origin cell, and carries out signal transduction through G-albumen coupling signal transduction thus mediate their chemical attractants and chemical stimulation function.Receptor may in conjunction with more than a kind of part, such as, receptor CCR1 is in conjunction with RANTES (normal T-cell express activation regulate), MIP-1 α (macrophage inflammatory protein), MPIF-1/CK β 8 and leucotaxin chemotactic factor (and compared with low-affinity other).So far known 24 kinds of chemotactic factors.The absolute quantity of chemotactic factor, multiple ligands bind receptor, and the distribution of different on immunocyte receptor can be carried out strictly controlled with specific immunoreation.See Rossi etc., Ann.Rev.Immunol.18 (1): 217-242 (2000).Chemotactic factor activity can be undertaken being controlled by regulating their corresponding receptors, and treatment related inflammation and immunological diseases also can carry out organizing and organ transplantation.
Receptor CCR1 and its chemokine ligand, comprise, such as MIP-1 α, MPIF-1/CK β 8, leucotaxin and RANTES represent effective therapy target (see Saeki etc., Current Pharmaceutical Design 9:1201-1208 (2003)), because they participate in rheumatoid arthritis, graft rejection reaction (see DeVries, M.E. etc., the same) and multiple sclerosis (see Fischer etc., J Neuroimmunol.110 (1-2): 195-208 (2000); Izikson etc., J.Exp.Med.192 (7): 1075-1080 (2000); With Rottman etc., Eur.J.Immunol.30 (8): 2372-2377 (2000)).In fact, had been found that function blocking antibody, modification chemokine receptor ligands and little organic compound, some of them successfully prove to prevent or to treat some chemokine mediated disease (at Rossi etc., with upper summary).It should be noted that, in the experimental model of rheumatoid arthritis, when using signal transduction blocking-up, modification RANTES part, disease progression weakens (see Plater-Zyberk etc., Immunol Lett.57 (1-3): 117-120 (1997)).Although function blocking antibody and the treatment of little peptide are likely, they have the risk of degraded, once it is extremely short to use the half-life, high expense hinders exploitation and manufactures, and these are features of most of albumen.Little organic compound is preferred, because they usually have the longer half-life in vivo, needs less dosage to obtain effect, usually can be oral, and therefore more cheap.Previously some organic antagonists of CCR1 was described (see Hesselgesser etc., J.Biol.Chem.273 (25): 15687-15692 (1998); Ng etc., J.Med.Chem.42 (22): 4680-4694 (1999); Liang etc., J.Biol.Chem.275 (25): 19000-19008 (2000) and Liang etc., Eur.J.Pharmacol.389 (1): 41-49 (2000)).In view of the effectiveness of the disease therapy proved in animal model is (see Liang etc., J.Biol.Chem.275 (25): 19000-19008 (2000)), continue to study thus identified other compounds that may be used for the disease for the treatment of the mediation of CCR1 signal transduction.
Brief summary of the invention
The present invention relates to the compound shown in formula I:
Or its pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer.In formula I, alphabetical n is the integer of 0-3;
Each A is independently selected from N or CH;
X and Z is independently selected from lower group separately:
(i) monocycle or fused bicyclic aryl and heteroaryl, wherein heteroaryl have be selected from N, O and S 1-4 hetero atom as ring members;
(ii) be selected from the monocycle four of cycloalkanes or heterocycle alkane-, five-, six-or seven-ring, wherein assorted naphthenic ring have be selected from N, O and S 1-3 hetero atom as ring members;
Each ring wherein in (i) and (ii) is optionally selected from 1-5 the substituent group replacement of lower group: halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-SO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocycle alkane, hetero atom wherein as the ring summit of heteroaryl and assorted naphthenic ring is selected from N, O and S, and wherein substituent alkyl, cycloalkyl, aryl, heteroaryl and heterocycle alkane moiety are further by 1-3 R areplace, and optionally, two substituent groups on adjacent ring summit are connected thus form extra 5-or 6-ring, and it is saturated, undersaturated or fragrant, and have the ring summit being selected from C, O, N and S;
R 3be selected from lower group: H, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocyclic radical, the hetero atom wherein as the ring summit of heteroaryl and heterocycle is selected from N, O and S, and wherein R 3alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties optional further by 1-3 R areplace;
R 4be selected from lower group: H ,-OR aoptionally by-OR athe C replaced 1-8alkyl;
R 9be selected from lower group: H and optionally by-OR athe C replaced 1-8alkyl;
Each R aand R bindependently be selected from lower group: hydrogen, hydroxyl, halogen, cyano group, C 1-8alkyl, C 1-8alkoxyl, C 1-8haloalkyl, C 3-6cycloalkyl, C 3-6cycloalkyl-alkyl, amino, C 1-8alkyl amino, two C 1-8alkyl amino, carbamyl (carboxamide), carboxyl C 1-4arrcostab, carboxylic acid and-SO 2-C 1-8alkyl.
Except compound provided herein, the present invention goes back the pharmaceutical composition of providing package containing one or more these compounds, and the using method of these compounds, primary treatment relevant disease active in CCR1 signal transduction.
Accompanying drawing explanation
Nothing
Detailed Description Of The Invention
I. abridge and define
Unless otherwise mentioned, term " alkyl " itself or refer to that there is appointment carbon number (i.e. C as another substituent part 1- 8refer to 1-8 carbon) straight or branched alkyl.The example of alkyl comprises methyl, ethyl, n-propyl group, isopropyl, n-butyl, t-butyl, isobutyl group, sec-butyl, n-amyl group, n-hexyl, n-heptyl, n-octyl group etc.Term " thiazolinyl " refers to the unsaturated alkyl with one or more double bond.Equally, term " alkynyl " refers to the unsaturated alkyl with one or more triple bond.The example of this unsaturated alkyl comprises vinyl, 2-acrylic, crotyl, 2-isopentene group, 2-(butadienyl), 2,4-pentadienyl, 3-(Isosorbide-5-Nitrae-pentadienyl), acetenyl, 1-and 3-propinyl, 3-butynyl and more higher homologue and isomers.Term " cycloalkyl " refers to have hydrocarbon ring (the such as C specifying annular atoms number 3-6cycloalkyl), be completely saturated or there is a no more than double bond between ring summit." cycloalkyl " also refers to dicyclo and polycyclic hydrocarbon ring, such as, and bicyclo-[2.2.1] heptane, bicyclo-[2.2.2] octane etc.Term " heterocycle alkane " or " Heterocyclylalkyl " refer to comprise one to five the heteroatomic cycloalkyl being selected from N, O or S, and wherein, nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heterocycle alkane can be monocycle, dicyclo or multi-ring loop systems.The unrestricted example of heterocycle alkane comprises pyrrolidine, imidazolidine, pyrazolidine, butyrolactam, valerolactam, imidazolidinone, hydantoin, dioxolanes, phthalimide, piperidines, 1,4-dioxane, morpholine, thiomorpholine, thiomorpholine-S-oxide, thiomorpholine-S, S-oxide, piperazine, pyrans, pyridone, 3-pyrrolin, thiapyran, pyrone, oxolane, Tetramethylene sulfide, quinuclidine etc.Heterocyclylalkyl can be connected to the remainder of molecule by ring carbon or hetero atom.
Term " alkylidene " itself or as another substituent part, refers to the divalent group derived from alkane, such as-CH 2cH 2cH 2cH 2-.Usually, alkyl (or alkylidene) has 1-24 carbon atom, and the present invention preferably has these groups of 10 or less carbon atoms." low alkyl group " or " low-grade alkylidene " is comparatively short-chain alkyl or alkylidene, usually has 4 or less carbon atoms.Similarly, " alkenylene " and " alkynylene " refers to " alkylidene " of the unsaturated form with double bond or triple bond respectively
As used herein, the wave crossing with singly-bound, double bond or triple bond in any chemical constitution that the present invention describes, represent singly-bound, double bond or the triple bond junction point to molecule remainder.
Term " alkoxyl ", " alkyl amino " and " alkylthio group " (or thio alkoxy) use with their conventional sense, refer to those alkyl being connected to the remainder of molecule by oxygen atom, amino or sulphur atom respectively.In addition, for dialkyl amido, moieties can be identical or different, also can be combined with the nitrogen-atoms connected separately thus form 3-7 ring.Therefore, dialkyl amido or-NR ar bshown group comprises piperidyl, pyrrolidinyl, morpholinyl, azelidinyl etc.
Term " two-(C 1-4alkyl) amino-C 1-4alkyl " refer to can be identical or different two C 1-4the amino of alkyl (as methyl, ethyl, propyl group, isopropyl, normal-butyl, sec-butyl, isobutyl group and the tert-butyl group), and pass through C 1-4alkyl (the alkylidene linking group of 1-4 carbon) is connected to the remainder of molecule.Two-(C 1-4alkyl) amino-C 1-4the example of alkyl comprises dimethylaminomethyl, 2-(ethyl (methyl) is amino) ethyl, 3-(dimethylamino) butyl etc.
Unless otherwise mentioned, term " halo " or " halogen " itself or refer to fluorine, chlorine, bromine or iodine atom as another substituent part.In addition, term comprises single haloalkyl and multi-haloalkyl as " haloalkyl " refers to.Such as, term " C 1- 4haloalkyl " refers to and comprises trifluoromethyl, 2,2,2-trifluoroethyls, 4-chlorobutyl, 3-bromopropyl etc.
Unless otherwise mentioned, term " aryl " refers to polyunsaturated, normally the alkyl of fragrance, can be monocycle or condenses together or covalently bound multi-ring (at the most three rings).Term " heteroaryl " refers to 1-5 the heteroatomic aryl (or ring) comprising and be selected from N, O or S, and wherein nitrogen and sulphur atom are optionally oxidized, and nitrogen-atoms is optionally quaternized.Heteroaryl can be connected to the remainder of molecule by hetero atom.The unrestricted example of aryl comprises phenyl, naphthyl and xenyl, and the unrestricted example of heteroaryl comprises pyridine radicals, pyridazinyl, pyrazinyl, pyrimidine radicals, triazine radical, quinolyl, quinoxalinyl, quinazolyl, cinnolines base, phthalazinyl, phentriazine base, purine radicals, benzimidazolyl, benzopyrazoles base, benzotriazole base, benzoisoxazole base, isobenzofuran-base, isoindolyl, indolizine base, phentriazine base, thienopyridine base, Thienopyrimidine base, pyrazolopyrimidine base, imidazopyridine, benzothiazolyl, benzofuranyl, benzothienyl, indyl, quinolyl, isoquinolyl, isothiazolyl, pyrazolyl, indazolyl, pteridyl, imidazole radicals, triazolyl, tetrazole radical, oxazolyl, isoxazolyl, thiadiazolyl group, pyrrole radicals, thiazolyl, furyl, thienyl etc.Above-mentioned each aryl and heteroaryl ring-member substituent group are separately selected from and following accept substituent group
Term " aryl alkyl " refers to that the aryl comprised wherein is connected to those groups (as benzyl, phenethyl etc.) of alkyl.Similarly, term " heteroaryl-alkyl " refers to that the heteroaryl comprised wherein is connected to those groups (as picolyl, thiazolylethyl etc.) of alkyl.
In some embodiments, above term (as " alkyl ", " aryl " and " heteroaryl ") will comprise the replacement of indication group and not replace form.The preferred substituents of all types of group is below provided.
Substituent group on alkyl (comprising those groups being commonly referred to alkylidene, thiazolinyl, alkynyl and cycloalkyl) can be selected from the various different group of lower group :-halogen ,-OR ' ,-NR ' R " ,-SR ' ,-SiR ' R " R " ' ,-OC (O) R ' ,-C (O) R ' ,-CO 2r ' ,-CONR ' R " ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR '-C (O) NR " R " ' ,-NR " C (O) 2r ' ,-NH-C (NH 2)=NH ,-NR ' C (NH 2)=NH ,-NH-C (NH 2)=NR ' ,-S (O) R ' ,-S (O) 2r ' ,-S (O) 2nR ' R " ,-NR ' S (O) 2r " ,-CN and-NO 2, quantity is from 0 to (2m '+1), and wherein m ' is the total number of carbon atoms in this alkyl (comprising those groups being commonly referred to alkylidene, thiazolinyl, alkynyl and cycloalkyl).R ', R " and R " ' be independently hydrogen, unsubstituted C separately 1-8alkyl, unsubstituted aryl, the aryl of a 1-3 halogen substiuted, unsubstituted C 1-8alkyl, C 1-8alkoxyl or C 1-8thio alkoxy or unsubstituted aryl-C 1-4alkyl.As R ' and R " when being connected to same nitrogen-atoms, they can combine with nitrogen-atoms thus form 3-, 4-, 5-, 6-or 7-ring.Such as ,-NR ' R " refer to and comprise 1-pyrrolidinyl and 4-morpholinyl.
Similarly, the substituent group on aryl and heteroaryl is various, is usually selected from lower group :-halogen ,-OR ' ,-OC (O) R ' ,-NR ' R " ,-SR ' ,-R ' ,-CN ,-NO 2,-CO 2r ' ,-CONR ' R " ,-C (O) R ' ,-OC (O) NR ' R " ,-NR " C (O) R ' ,-NR " C (O) 2r ' ,-NR '-C (O) NR " R " ' ,-NH-C (NH 2)=NH ,-NR ' C (NH 2)=NH ,-NH-C (NH 2)=NR ' ,-S (O) R ' ,-S (O) 2r ' ,-S (O) 2nR ' R " ,-NR ' S (O) 2r " ,-N 3, perfluor (C 1-C 4) alkoxyl and perfluor (C 1-C 4) alkyl, quantity opens the sum of chemical valence from 0 to aromatic rings system, wherein, and R ', R " and R " ' be independently selected from hydrogen, C 1-8alkyl, C 1-8haloalkyl, C 3-6cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, unsubstituted aryl and heteroaryl, (unsubstituted aryl)-C 1-4alkyl and unsubstituted aryloxy group-C 1-4alkyl.Other suitable substituent groups comprise above each aryl substituent and are connected to annular atoms by the alkylidene chain of 1-4 carbon atom.
Two in substituent group on aryl or heteroaryl ring adjacent atom can optionally by formula-T-C (O)-(CH 2) qthe substituent group of-U-substitutes, and wherein T and U is independently-NH-,-O-,-CH 2-or singly-bound, and q is the integer of 0-2.Or two in the substituent group on aryl or heteroaryl ring adjacent atom can optionally by formula-A-(CH 2) r-B-substituent group substitutes, and wherein A and B is independently-CH 2-,-O-,-NH-,-S-,-S (O)-,-S (O) 2-,-S (O) 2nR '-or singly-bound, and r is the integer of 1-3.One of singly-bound of the new ring of such formation can optionally be substituted by double bond.Or two in the substituent group on aryl or heteroaryl ring adjacent atom can optionally by formula-(CH 2) s-X-(CH 2) t-substituent group substitutes, and wherein s and t is independently the integer of 0-3, and X is-O-,-NR '-,-S-,-S (O)-,-S (O) 2-or-S (O) 2nR '-.-NR '-and-S (O) 2nR '-in substituent R ' be selected from hydrogen or unsubstituted C 1- 6alkyl.
As used herein, term " hetero atom " refers to and comprises oxygen (O), nitrogen (N), sulfur (S) and silicon (Si).
Term " pharmaceutically acceptable salt " refers to the salt comprising reactive compound, according to substituent group specific on compound described herein, adopts acid or the alkali preparation of relative nontoxic.When compound of the present invention comprises relatively acid functional group, can by by this compound of neutral form with enough needed for alkali or direct or contact to obtain base addition salts in suitable atent solvent.Example derived from the salt of pharmaceutically acceptable inorganic base comprises aluminum, ammonium, calcium, copper, ferrum, ferrous, lithium, magnesium, manganese, sub-manganese, potassium, sodium, zinc etc.Salt derived from pharmaceutically acceptable organic base comprises primary, the salt of the second month in a season and tertiary amine, comprise the amine of replacement, cyclammonium, naturally occurring amine etc., as arginine, betanin, caffeine, gallbladder alkali, N, N '-dibenzyl-ethylenediamin, diethylamine, 2-diethylaminoethanol, DMAE, ethanolamine, ethylenediamine, N-ethylmorpholine, N-ethylpiperidine, glycosamine, glucosamine, histidine, breathe out amine (hydrabamine), 2-aminopropane., lysine, methylglucosamine, morpholine, piperazine, piperidines, polyamino resin, procaine, purine, theobromine, triethylamine, trimethylamine, tripropyl amine (TPA), trometamol etc.When compound of the present invention comprises the functional group of alkalescence relatively, can by by this compound of neutral form and enough required acid or direct or contact to obtain acid-addition salts in suitable atent solvent.The example of pharmaceutically acceptable acid-addition salts comprises derived from those of mineral acid, example hydrochloric acid, hydrobromic acid, nitric acid, carbonic acid, a hydrogen carbonic acid, phosphoric acid, a hydrogen phosphoric acid, dihydrogen phosphoric acid, sulphuric acid, a hydrosulphuric acid, hydroiodic acid or phosphorous acid etc., with the organic acid salt derived from relative nontoxic, as acetic acid, propanoic acid, isopropylformic acid., malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, mandelic acid, phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid, pyrovinic acid etc.Also comprise the salt of aminoacid as arginine etc., and organic acid is as the salt (see such as, Berge, S.M. etc., " pharmaceutical salts ", Journal of Pharmaceutical Science, 1977,66,1-19) of glucuronic acid or galacturonic acid etc.Some specific compound of the present invention comprises alkalescence and acidic functionality simultaneously, makes compound can change into alkali or acid-addition salts.
Contact by salt with alkali or acid and be separated the compound that parent compound can regenerate neutral form in conventional manner.The parent fo of compound is different from various salt form in some physical property, and as the dissolubility in polar solvent, but in addition, for object of the present invention, salt is equal to the compound of parent fo
Except salt form, the invention provides the compound of prodrug forms.The prodrug of compound described herein easily experiences chemical change in physiological conditions to provide those of the compounds of this invention.In addition, prodrug is converted into the compounds of this invention by chemistry or biochemical method in ex vivo environment.Such as, when being placed in transdermal patch together with suitable enzyme or chemical reagent, prodrug slowly can be converted into the compounds of this invention.
Some compound of the present invention can with nonsolvated forms and the solvation form existence comprising hydrated form.Usually, solvation form is equal to nonsolvated forms, and comprises within the scope of the present invention.Polymorphic or amorphous form can be there is in some compound of the present invention.Usually, for the application of the present invention's expection, all physical form are equivalent, and comprise within the scope of the present invention.
Some compound of the present invention has asymmetric carbon atom (optical center) or double bond; Racemic modification, diastereomer, geometric isomer, regional isomer and single isomer (such as, different enantiomer) are included in the scope of the invention.Compound of the present invention can also contain the atom isotope of unnatural proportions at the one or more atom places forming these compounds.The isotope of unnatural proportions can be defined as amount that occurring in nature finds to formation 100% the amount of atom is discussed.Such as, this compound can mix radiosiotope, such as tritium ( 3h), iodine-125 ( 125i) or carbon-14 ( 14c) or non radioactive isotope, as deuterium ( 2h) or carbon-13 ( 13c).This isotopic change can provide other effectiveness for those of the application other places description.Such as, the isotopic variations of the compounds of this invention can find extra purposes, includes but not limited to, as diagnostic agent and/or preparation, or as cytotoxic agent/radiotoxicity therapeutic agent.In addition, the isotopic variations of the compounds of this invention can have and can strengthen safety, the pharmacokinetics of change of toleration or effect and pharmacodynamic profile at treatments period.No matter whether all isotopic variations of the compounds of this invention, be radioactive, be intended to be contained in the scope of the invention.
Unless otherwise mentioned, term " and isostere (isosteres) of acid " refers to the group that can substitute carboxylic acid, the space of the sense with acid and the activity level providing similar carboxylic acid and electronic characteristic (or other compound characteristics are as dissolubility).The isostere of representational acid comprises: hydroxamic acid, sulfonic acid, sulfinic acid, sulfonamide, acyl group-sulfonamide, phosphonic acids, phosphinic acid, phosphoric acid, tetrazolium and oxygen-oxadiazole.
Compound described in formula I can be different isomers form exist.As used herein, term cis or transly to be used with chemical field conventional sense, namely refer to relative to reference plane, as double bond or loop systems, as naphthalane type loop systems or hydrogen quinolinones (hydroquinolone) loop systems, substituent group position each other: in cis-isomer, substituent group is at the homonymy of reference plane, in transisomer, substituent group is at opposite side.In addition, different conformers and different rotamers are contained in the present invention.Conformer is can by rotating the conformer of the about one or more σ key of difference.Rotamer is the conformer that over-rotation differs about only single σ key.
I. summarize
The present invention comes from the potent antagonist of the compound shown in discoverable type I as CCR1 receptor.Described compound has interior anti-inflammatory activity and excellent pharmacokinetic property.Therefore, compound provided herein is useful in the pharmaceutical composition being used for the treatment of the disease that CCR1 mediates and method, and can with comparing in the test of the competitive CCR1 antagonist of qualification.
III. compound
In one aspect, the invention provides the compound shown in formula I:
Or its pharmaceutically acceptable salt, hydrate, solvate, N-oxide or rotamer.In formula I, alphabetical n is the integer of 0-3;
Each A is independently selected from N or CH;
X and Z is independently selected from lower group separately:
(i) monocycle or fused bicyclic aryl and heteroaryl, wherein heteroaryl have be selected from N, O and S 1-4 hetero atom as ring members;
(ii) be selected from the monocycle four of cycloalkanes or heterocycle alkane-, five-, six-or seven-ring, wherein assorted naphthenic ring have be selected from N, O and S 1-3 hetero atom as ring members;
Each ring wherein in (i) and (ii) is optionally selected from 1-5 the substituent group replacement of lower group: halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-SO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocycle alkane, hetero atom wherein as the ring summit of heteroaryl and assorted naphthenic ring is selected from N, O and S, and wherein substituent alkyl, cycloalkyl, aryl, heteroaryl and heterocycle alkane moiety are further by 1-3 R areplace, and optionally, two substituent groups on adjacent ring summit are connected thus form extra 5-or 6-ring, and it is saturated, undersaturated or fragrant, and have the ring summit being selected from C, O, N and S;
R 3be selected from lower group: H, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocyclic radical, the hetero atom wherein as the ring summit of heteroaryl and heterocycle is selected from N, O and S, and wherein R 3alkyl, cycloalkyl, aryl, heteroaryl and heterocyclyl moieties optional further by 1-3 R areplace;
R 4be selected from lower group: H ,-OR aoptionally by-OR athe C replaced 1-8alkyl;
R 9be selected from lower group: H and optionally by-OR athe C replaced 1-8alkyl;
Each R aand R bindependently be selected from lower group: hydrogen, hydroxyl, halogen, cyano group, C 1-8alkyl, C 1-8alkoxyl, C 1-8haloalkyl, C 3-6cycloalkyl, C 3-6cycloalkyl-alkyl, amino, C 1-8alkyl amino, two C 1-8alkyl amino, carbamyl, carboxyl C 1-4arrcostab, carboxylic acid and-SO 2-C 1-8alkyl.
In the embodiment that some are selected, shown in the formula Ia of formula I or its pharmaceutically acceptable salt, hydrate, solvate, rotamer or N-oxide:
Wherein A 1for N or C (R 5); A 2for N or C (R 7); R 5, R 6, R 7and R 8independently be selected from lower group: H separately, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocycle alkane, the hetero atom wherein as the ring summit of heteroaryl and assorted naphthenic ring is selected from N, O and S, wherein R 5, R 6, R 7and R 8alkyl, cycloalkyl, aryl, heteroaryl and heterocycle alkane moiety be further by 1-3 R areplace; And optionally, R 5, R 6, R 7and R 8neighbor members be connected thus form extra 5-or 6-ring, it is saturated, undersaturated or fragrant and has the ring summit being selected from C, O, N and S.
In the embodiment that other are selected, the compound of formula I is R 8not those of H.
In the embodiment that other are selected, shown in the formula Ib of formula I:
Wherein R 1and R 2independently be selected from lower group: H separately, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-SO 2r a,-NR ar b,-CONR ar bwith 3-, 4-, 5-or 6-unit heterocycle alkane, the hetero atom wherein as the ring summit of naphthenic ring of mixing is selected from N, O and S, and wherein R 1and R 2alkyl, cycloalkyl and heterocycle alkane moiety be further by 1-3 R areplace.
In the embodiment that formula Ib selects, each R 1and R 2independently be selected from lower group: H, halogen, CN, C 1-8alkyl, C 1-8haloalkyl ,-CO 2r awith-SO 2r a.
In other embodiments selected of the compound shown in formula Ib, N, A 1and A 2loop section as ring summit is selected from:
In other embodiments selected of the compound shown in the formula Ib also had, N, A 1and A 2loop section as ring summit is selected from:
Wherein R 7for H or Cl, R 8for optionally by 1 or 2 R athe C replaced 1-8alkyl.
In other embodiments selected of the formula Ib also had, R 9for H or CH 3.
Get back to formula I, some embodiments selected are those compounds represented by formula Ic:
Wherein alphabetical n is 1,2 or 3.Other embodiments selected to be n be 1 those.
In other embodiments selected also had, the compound shown in formula Ib is those that represented by formula Ib1:
Wherein R 1for Cl or F.
In other embodiments selected also had, shown in formula Ib1a, Ib1b and the Ib1c shown in formula Ib1:
In some embodiments selected of formula Ib, shown in formula Ib2:
Wherein R 1for Cl or F.
In some embodiments selected of formula Ib, shown in formula Ib3a, Ib3b and Ib3c:
In the embodiment of formula I, any one selection of Ia, Ib, Ic, Ib1, Ib1a, Ib1b, Ib1c, Ib2, Ib3a, Ib3b and Ib3c, R 3be selected from lower group: H, C 1-8alkyl, C 3-8cycloalkyl and C 2-8thiazolinyl.
prepared by compound
The scheme of following examples provides some route of synthesis that can obtain some compound of the present invention by it.The amendment of other approach or following approach will be apparent for a person skilled in the art, and within the scope of the present invention.
IV. pharmaceutical composition
Except the compound provided above, usually comprise pharmaceutical carrier or diluent for regulating the compositions of human and animal CCR1, CCR2 and CCR3 activity.
As used herein, term " compositions " is intended to comprise the product of the special component comprising certain content, and the direct or indirect any product be made up of the combination of the special component of certain content." pharmaceutically acceptable " refers to that carrier, diluent or excipient must be harmless to its receiver with other component compatibility of preparation.
Can exist with unit dosage forms easily for using the compounds of this invention pharmaceutical composition, and can by any known method preparation of pharmaceutics and drug delivery field.All methods comprise makes active component and the carrier-bound step forming one or more auxiliary elements.Usually, by equably and closely by active component and liquid-carrier or solid carrier in small, broken bits or both are in conjunction with pharmaceutical compositions, then, if necessary, product is made to be configured as required preparation.Active Target Compounds is to be included in pharmaceutical composition according to the progress of disease or enough amounts of the required effect of disease acquisition.
Pharmaceutical composition containing active component can be the form being suitable for orally using, such as, as tablet, and dragee, lozenge, aqueous or oily suspensions, dispersible powder or granule, U.S. Patent number 6,451, the Emulsion described in 339 and self-emulsifier, hard or soft capsule, syrup, elixir, solution, buccal bioadhesive tablet, oral gel, chewing gum, chewable tablet, effervescent powder and effervescent tablet.Can according to any method of pharmaceutical compositions known in the art for the preparation of the compositions orally used, for providing pharmaceutical elegant and good to eat preparation, said composition can comprise the medicament that one or more are selected from lower group: sweeting agent, flavoring agent, coloring agent, antioxidant and antiseptic.Tablet comprises active component, acceptable mixed with excipients on the non-toxic pharmaceutical prepared with applicable tablet.These excipient can be, such as, inert diluent, as cellulose, silicon dioxide, aluminium oxide, calcium carbonate, sodium carbonate, glucose, mannitol, sorbitol, lactose, calcium phosphate or sodium phosphate; Granulating agent and disintegrating agent, such as, corn starch or alginic acid; Bonding agent, such as PVP, cellulose, PEG, starch, gelatin or arabic gum; And lubricant, such as magnesium stearate, stearic acid or Talcum.Tablet can be non-coating or they can by known technology by coating, enteric or otherwise, to postpone disintegrate in the gastrointestinal tract and absorption, thus provides the continuous action of long term.Such as, material can be postponed service time as glyceryl monostearate or distearin.They can be also 4,256 by U.S. Patent number, 108,4,166,452 and 4,265, and the method described in 874 is carried out coating thus is formed the osmotic therapeutic tablets for Co ntrolled release.
The preparation orally used can also be rendered as hard gelatin capsule, and wherein active component mixes with inert solid diluent, such as, calcium carbonate, calcium phosphate or Kaolin, or be rendered as Perle, wherein active component mixes with water or oily medium, such as Oleum Arachidis hypogaeae semen, liquid paraffin or olive oil.In addition, Emulsion can be prepared with the mixable composition of non-water such as oil, and adopts surfactant as list-two glyceride, and macrogol ester etc. are stablized.
Waterborne suspension contains active substance, is mixed with the excipient being suitable for preparing waterborne suspension.Such excipient is suspending agent, such as sodium carboxymethyl cellulose, methylcellulose, hydroxypropyl cellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and Radix Acaciae senegalis: dispersant or wetting agent can be naturally occurring phospholipid, such as lecithin, or the condensation product of alkylene oxide and fatty acid, such as Myrj 45, or the condensation product of oxirane and long chain aliphatic, such as 17 ethyleneoxy hexadecanol, or oxirane and the condensation product of partial ester that derived by fatty acid and hexitol, as polyoxyethylene 80 sorbitan monooleate, or oxirane and the condensation product of partial ester that derived by fatty acid and hexitan, such as polyethylene sorbitan monoleate.Waterborne suspension also can contain one or more antiseptic, such as ethylparaben or n-propyl, one or more coloring agent, and one or more flavoring agents, and one or more sweeting agents, as sucrose or glucide.
Oily suspensions by active component is suspended in vegetable oil, such as Oleum Arachidis hypogaeae semen, olive oil, Oleum sesami or Oleum Cocois, or at mineral oil as liquid paraffin is prepared.Oily suspensions can contain thickening agent, such as Cera Flava, hard paraffin or spermol.Can sweeting agent be added, as listed above those, and flavoring agent is to provide good to eat oral formulations.These compositionss can by adding antioxidant, and such as ascorbic acid is preserved.
Be applicable to by adding water and prepare the dispersed powders of waterborne suspension and granule providing active component and dispersant or wetting agent, the mixing of suspending agent and one or more antiseptic.Suitable dispersion or wetting agent and suspending agent are by illustrating of having mentioned above.Also other excipient can be there is, such as sweeting agent, flavoring agent and coloring agent.
Pharmaceutical composition of the present invention also can be oil in water emulsion form.Oil phase can be vegetable oil, such as olive oil or Oleum Arachidis hypogaeae semen, or mineral oil, such as liquid paraffin or these mixture.Suitable emulsifying agent can be naturally occurring natural gum, such as Radix Acaciae senegalis or gum tragacanth, naturally occurring phospholipid, such as Semen sojae atricolor, lecithin and by the derivative ester of fatty acid and hexitan or partial ester, such as monooleate sorbitan ester, the condensation product of described partial ester and oxirane, such as Tween-81.Emulsion also can contain sweeting agent and flavoring agent.
Syrup and elixir can be prepared with sweeting agent, such as glycerol, propylene glycol, sorbitol or sucrose.Such preparation can also contain demulcent, antiseptic and flavoring agent and coloring agent.Oral administration solution can with such as, cyclodextrin, PEG and the incompatible preparation of group of surfactants.
Pharmaceutical composition can be the form of sterile injectable aqueous or oily suspensions.This suspension can use those suitable dispersants as above or wetting agent and suspending agent agent to prepare according to known technology.Aseptic injection preparation can also be sterile injectable solution in the acceptable diluent of nontoxic parenteral or solvent or suspension, such as, solution in 1,3 butylene glycol.Operable acceptable vehicle and solvent are water, Ringer's mixture and isotonic sodium chlorrde solution.In addition, aseptic fixed oil is typically used as solvent or suspension media.For this purpose, the fixing oil of any gentleness can use, and comprises the list-of synthesis or two acid anhydride ester.In addition, fatty acid such as oleic acid also can be used for the preparation of injection.
Compound of the present invention also suppository form can be used for rectally.These compositionss can by being prepared medicine and suitable non-irritating mixed with excipients, and this excipient is solid at normal temperatures, but is liquid under rectal temperature, therefore will melt in the rectum to discharge medicine.Such material comprises cocoa butter and Polyethylene Glycol.In addition, this compound solution or ointment can send administration by eye.Further, the dermal delivery of the compounds of this invention is realized by iontophoresis patch etc.Local is used, uses the cream containing compound of the present invention, ointment, gel, solution or suspension etc.As used herein, topical application is also intended to comprise and uses collutory and gargarism.
Compound of the present invention can be prepared and be used for depositing in medical treatment device, and medical treatment device can comprise any various conventional graft, and support, comprises stent graft, conduit, balloon, basket maybe can arrange or Permanent implantation at other devices endoceliac.As special example, may wish can by compound delivery of the present invention extremely through the apparatus and method of the body region of interventional technique treatment.
In the exemplary embodiment, inhibitor of the present invention can be deposited on medical treatment device as in support, and is delivered to the treatment of therapentic part for body part.
Support has been used as the delivery vector of therapeutic agent (i.e. medicine).Endovascular support is normally in the crown or peripheral vessels of Permanent implantation.Support Design comprises the U.S. patent No. 4,733,655 (Palmaz), 4,800,882 (Gianturco) or 4,886, those in 062 (Wiktor).These designs comprise metal and polymer support, and self-expanding and air bag expanding stent.Support is also used in the site delivering drugs contacted with vascular system, as with Publication about Document those disclosed: the U.S. patent No. 5,102,417 (Palmaz), international patent application no WO 91/12779 (Medtronic Inc. (Medtronic,) and WO 90/13332 (Cedars-Sanai medical centre), the U.S. patent No. 5 Inc.), 419,760 (Narciso, and the U.S. patent No. 5 Jr.), 429,634 (Narciso, Jr.).Support also for sending virus to the wall of inner chamber with delivery of gene, as U.S. Patent Application Serial 5, disclosed in 833,651 (Donovan etc.).
Term " deposition " refer to by methods known in the art by inhibitor coated, absorption, place or be otherwise attached to device.Such as, inhibitor can embed in the polymeric material and discharge (" matrix type ") from its inside, or can by polymer material encases and by polymeric material release (" reservoir devices "), described coating polymeric materials or leap (span) medical treatment device.In a rear example, one or more can be used for generation of the technology of this kind of material as known in the art, inhibitor be captured in polymeric material or combine (couple) to polymeric material.In other preparation, inhibitor can not need coating and is connected to the surface of medical treatment device by removable key and discharges in time, by machinery initiatively or chemical process removing, or makes inhibitor be in the form be permanently fixed of transplanted sites.
In one embodiment, during medical treatment device forms biocompatible coating as support, inhibitor can be combined with polymers compositions.The coating formed by these components is normally uniform, can be used for applying the multiple device being designed for transplanting.
Polymer can be Biostatic or can the polymer of bio-absorbable, depend on required rate of release or required polymer stabilizing degree, but can the polymer of bio-absorbable be preferred to present embodiment, because, be different from Biostatic polymer, it can not exist for a long time after the transfer thus cause any bad, chronic local response.Available the polymer of bio-absorbable can include, but not limited to PLLA, polycaprolactone, PGA (PGA), (lactide coglycolide) copolymer (PLLA/PGA), poly-(butyric ester), (hydroxybutyrate-co-valerate) copolymer, Ju diethyleno dioxide ketone, poe, polyanhydride, poly-(glycolic), poly-(D-ALPHA-Hydroxypropionic acid), PLLA, poly-(D, Pfansteihl), PLA (PLA), poly-(L-lactide) (PLLA), (glycolic-trimethylene carbonate) copolymer (PGA/PTMC), poly(ethylene oxide) (PEO), Ju diethyleno dioxide ketone (PDS), poly phosphate, polyphosphoester urethane, poly-(aminoacid), cyanoacrylate, poly-(trimethylene carbonate), poly-(iminocarbonic ester), copolymerization (ether-ester) (such as, PEO/PLA), poly-oxalic acid alkylene carbonate, polyphosphazene and biomolecule, as fibrin, Fibrinogen, cellulose, starch, collagen and hyaluronic acid, poly epsilon caprolactone lactone, poly butyric, poe, polyacetals, poly-dihydropyran, polybutylcyanoacrylate, cross-linked hydrogel or hydrogel amphiphilic block copolymer, or known in the art other suitable can the polymer of bio-absorbable.In addition, there is the Biostatic polymer of relatively low chronic tissue's response, such as polyurethane, silicone and polyester also can use, and other polymer also can use, such as, if they can dissolve and solidify or be polymerized on the medical instrument, polyolefin, polyisobutylene and ethene-alpha-olefin copolymer; Acrylate copolymer and copolymer, vinyl halide polymer and copolymer, as polrvinyl chloride, polyvinylpyrrolidone; Polyvinylether, as polyvinyl methyl ether; Polyvinylidene halogenide (polyvinylidene halides), as polyvinylidene fluoride and polyvinylidene chloride; Polyacrylonitrile, polyethylene ketone; Polyvinyl arene, such as polystyrene, polyvinyl ester, as polyvinyl acetate; Vinyl monomer each other and the copolymer of alkene, as ethylene methyl methacrylate copolymer, acrylonitritrile-styrene resin, ABS resin, and vinyl-vinyl acetate copolymer; Pyran co-polymer; Poly-hydrox-propyl-methyl acrylamide-phenol; Polyhydroxyethyl-aspartarnide-phenol; The polyethyleneoxide-polylysine (polyethyleneoxide-polylysine substituted with palmitoyl residues) that palmitoyl residues replaces; Polyamide, as nylon66 fiber and polycaprolactam; Alkyd resins, Merlon; Polyformaldehyde; Polyimides; Polyethers; Epoxy resin, polyurethane; Artificial silk; Artificial silk-triacetate; Cellulose, cellulose acetate, cellulose butyrate; Butanoic acid cellulose acetate; Cellophane; Celluloid; Cellulose propionate; Cellulose ether; And carboxymethyl cellulose.
Polymer and semi-permeable polymer matrices can be processed into moulded products, as valve, and support, pipe, prosthese etc.
In an embodiment of the invention, inhibitor of the present invention is attached to the polymer or semi-permeable polymer matrices that are formed as support or stent-graft device.
Typically, by spin coating, dipping or spraying, polymer is applied to the surface of implantable device.Other method as known in the art also can be used for this purpose.Spraying method comprises traditional method, and the microdeposit technology of band inkjet type allotter.In addition, can use photoetching that polymer is only placed in the specific part of device by polymer deposition on implantable device.This coating of device provides the conforming layer around device, and it makes various analysis thing be improved by the diffusion of device coating.
In the preferred embodiment of the present invention, preparation inhibitor is used for being released into the environment of medical treatment device placement from polymer coating.Preferably, use at least one related in several known technologies of polymer support or layer, time range (e.g., the moon) release inhibitor in a controlled manner through extending, thus control eluting.Some these type of technology be previously described in U.S. Patent application 20040243225A1.
In addition, as described in U.S. Patent number 6770729, reagent and the reaction condition that can handle polymers compositions can be controlled from the release of polymer coating to make inhibitor.Such as, the diffusion coefficient of one or more polymer coatings can be regulated thus control inhibitor discharge from polymer coating.In the version of this scheme, can control one or more polymer coatings diffusion coefficient thus in the environment regulating medical treatment device to place the analysis thing (such as promoting the decomposition of the some parts of polymer or the analysis thing of hydrolysis) that exists close to the ability (and such as, thus regulate inhibitor from the release of polymer coating) of one or more components in polymers compositions.Another embodiment that the present invention also has comprises the device with multiple polymer coating, and each coating has multiple diffusion coefficient.In these embodiments of the present invention, inhibitor can be regulated to discharge from polymer coating by multiple polymer coating.
In other embodiments that the present invention also has, by the release from polymer coating of one or more Properties Control inhibitor of telomerized polymer component, the existence of as endogenous in one or more or the xenobiontics of one or more performances described, or alternatively, the pH of polymers compositions.Such as, the pH that can design some polymers compositions responsive polymer components declines thus release inhibitor.Or, the response existence of hydrogen peroxide of some polymers compositionss can be designed thus release inhibitor.
III. the method for the disease that CCR1 regulates is treated
The another aspect also had, the invention provides the disease for the treatment of CCR1 mediation or the Therapeutic Method of disease, the above-mentioned formula I for the treatment of effective dose is administered to the object suffering from this disease or disease by described method." object " defined herein comprises animal, as mammal, includes but not limited to, primates (such as, people), cattle, sheep, goat, horse, Canis familiaris L., cat, rabbit, rat, mice etc.
CCR1 provides the target of interference or Promote immunity cell function particular aspects, or more generally, disturbs to mammal as expressed relevant function with CCR1 in the various kinds of cell type of people.The compound of CCR1 is suppressed to be used in particular for as therapeutic purposes regulate mononuclear cell, macrophage, lymphocyte, granulocyte, NK cell, mastocyte, dendritic cell, and some immune-derived cell (such as, osteoclast) function.Therefore, the present invention relates to the compound (see Saeki etc., Current Pharmaceutical Design 9:1201-1208 (2003)) that can be used for preventing and/or treating various inflammatory and immunomodulatory disorder and disease.
Such as, can use suppress CCR1 one or more functions described compound thus suppress (namely alleviate or prevent) immune disorders be correlated with inflammation or cellular infiltration.As a result, one or more inflammatory process can be suppressed, as leukocyte infiltration or infiltration, chemotaxis, the release of exocytosis (such as, enzyme, histamine) or inflammatory mediator.Such as, monocyte infiltration can be suppressed to inflammation part (such as, affected joint in arthritis, or enter the CNS in MS) according to the inventive method.
Similarly, use the described compound of the one or more functions promoting CCR1 thus stimulate (induction or enhancing) inflammatory reaction, as leukocyte infiltration, chemotaxis, exocytosis (such as, enzyme, histamine) or the release of inflammatory mediator, thus cause the favorable incentive of inflammatory process.Such as, mononuclear cell can be raised with to bacterial-infection resisting.
The inventive method can be adopted to treat and inflammation, immunological diseases and the relevant disease of infection and disease.In one preferred embodiment, disease or disease are to regulate inflammation or autoimmune reaction, need to suppress or Promote immunity cell, such as mononuclear cell, macrophage, lymphocyte, granulocyte, NK cell, mastocyte, dendritic cell, or the disease of the effect of some immune-derived cell (such as, osteoclast) or disease.
In one group of embodiment, the disease of people or other species or disease, comprise chronic disease, and CCR1 function regulator can be adopted to treat.These diseases or disease comprise: (1) anaphylactic disease, as systemic anaphylaxis or allergy, and drug allergy, sting allergy and food anaphylaxis, (2) inflammatory bowel, as Crohn disease, ulcerative colitis, ileitis and intestinal inflammation, (3) vaginitis, (4) psoriasis and inflammatory dermatosis are as dermatitis, eczema, allergic dermatitis, allergic contact dermatitis, urticaria and pruritus, (5) vasculitis, (6) spondyloarthropathy, (7) scleroderma, (8) asthma and respiratory anaphylactic disease are as asthma, and sensitivity is panted, allergic rhinitis, allergy pneumonopathy etc., (9) autoimmune disease, as fibromyalgia, scleroderma, ankylosing spondylitis, juvenile rheumatoid arthritis, Still disease, multi-joint Rheumatoid Arthritis, few joint Rheumatoid Arthritis, polymyalgia rheumatica, high peace arthritis (Takuyasu arthritis), rheumatoid arthritis, psoriatic arthritis, osteoarthritis, polyarthritis, multiple sclerosis, systemic lupus erythematosus (sle), type i diabetes, type ii diabetes, type i diabetes (showing effect in the recent period), optic neuritis, glomerulonephritis etc., (10) graft-rejection, comprises allograft rejection and acute and chronic graft versus host disease), (11) fibrosis (as pulmonary fibrosis (i.e. idiopathic pulmonary fibrosis), interstitial pulmonary fibrosis), the fibrosis relevant to advanced renal disease, by radiation-induced fibrosis, renal interstitial fibrosis, upper subcutaneous (subepithelieal) fibrosis, scleroderma (progressive systemic sclerosis), hepatic fibrosis (comprise and being caused by ethanol or viral hepatitis), constitutional and Secondary cases liver cirrhosis, (12) acute and chronic pulmonary inflammatory (chronic obstructive pulmonary disease, chronic bronchitis, adult respiratory distress syndrome, infant respiratory distress syndrome, immune complex alveolitis) and (13) other diseases, wherein less desirable inflammatory reaction or immune disorders will be inhibited, as cardiovascular disease, comprise atherosclerosis, the vascular inflammation that tissue transplantation or restenosis (including but not limited to the restenosis inserted with angioplasty and/or support) period cause, other acute and chronic inflammation diseases, as myositis, neurodegenerative disease (such as, Alzheimer), encephalitis, meningitis, hepatitis, nephritis, sepsis, sarcoidosis, allergic conjunctivitis, otitis, sinusitis, the synovitis that arthroscopy causes, antihyperuricemic, wound, local anemia reperfusion injury, nasal polyp, preeclampsia, oral lichen planus, lucky Na-Bali (Guillina-Barre) syndrome, granulomatous diseases, relevant disease is produced to leptin (leptin), Behcet (Behcet ' s) syndrome and gout and the application in wound healing, (14) immune-mediated food anaphylaxis, as celiac disease and (15) osteoclast disorders disease, comprises osteoporosis, and the molten bone osteopathia as relevant in multiple myeloma with cancer.
In another group embodiment, CCR1 function regulator disease therapy or disease can be adopted.The example of the disease of CCR1 function regulator treatment to be employed comprises cancer (constitutional and transitivity) (e.g., multiple myeloma; Hata, H., leukemia and lymphoma (Leukemia & Lymphoma), 2005,46 (7); 967-972), cardiovascular disease, disease (the neoplastic disease that angiogenesis or neovascularization are worked wherein, retinopathy and degeneration of macula), infectious disease (viral infection, such as, HIV and bacteriological infection) and immunosuppressive disease as organ transplant conditions and skin transplant conditions.Term " organ transplant conditions " refers to and comprises bone marrow transplant conditions and solid organ (such as, kidney, liver, lung, heart, pancreas or its combination) transplanting disease.
Pharmaceutical composition of the present invention also can produce metalloproteases and cytokine in inflammation-inhibiting position, no matter is directly or indirectly (result as reducing cellular infiltration), thus provides benefit for the disease or disease being associated with these cytokines.
Therefore compound of the present invention is used for prevention and therapy inflammation and immunoregulatory disorder and disease.
Depend on disease to be treated and the situation of object, compound of the present invention is by oral, parenteral (such as, intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection, or implant) administration, by sucking spraying, nose, vagina, rectum, Sublingual or topical routes, and can be formulated in separately or together in suitable dosage unit preparations, described dosage unit preparations contains the pharmaceutically acceptable carrier of the usual non-toxic being suitable for each route of administration, adjuvant and vehicle.
It will be appreciated by those skilled in the art that regulate CCR1 activity reagent can in therapeutic scheme with other treatment agent and/or and chemotherapeutics or radiation coupling.In some cases, if not with present composition coupling, the amount of chemotherapeutics or radiation is sub-treatment.It will be appreciated by those skilled in the art that " coupling " can relate to the coupling in treating (namely two or more medicines as mixture administration, or still can make in both blood flows simultaneously at object at different time introducing object at least simultaneously or at least).In addition, compositions of the present invention can administration before or after the second therapeutic scheme, such as, before or after potion chemotherapy or radiation.
In treatment or the disease of preventing to need chemokine receptors to regulate, suitable dosage level is generally about 0.001 to 100 milligrams per kilogram of weight in patients every day, and it can with single dose or multiple dose administration.Preferably, dosage level will be that every day about 0.01 is to about 25mg/kg/ days; More preferably, every day about 0.05 is to about 10mg/kg/ days.Suitable dosage level can for every day about 0.01 be to about 25mg/kg/ days, and every day about 0.05 is to about 10mg/kg/ days, or about 0.1 arrives about 5mg/kg/ days.Within the scope of this, but dosage every day 0.005-0.05,0.05-0.5 or 0.5-5.0mg/kg.For oral administration, preferably provide compositions with the tablet form comprising 1.0-1000 milligram active component, the particularly active component of 1.0,5.0,10.0,15.0,20.0,25.0,50.0,75.0,100.0,150.0,200.0,250.0,300.0,400.0,500.0,600.0,750.0,800.0,900.0 and 1000.0 milligrams, regulates (symptomatic adjustment) with the symptom of patient to be treated being carried out to dosage.Compound can every day the administration of 1 to 4 time, preferably once a day or twice.
It should be understood, however, that and can to change for the concrete dosage level of any particular patient and dose frequency, and will many factors be depended on, comprise the activity of the particular compound of use, metabolic stability and the duration worked of this compound, the age of object, body weight, inherited character, general health, sex and diet, and administering mode and time, discharge rate, drug combination, and the order of severity of specified disease just connecing subject object.
The compounds of this invention, compositions can be adopted with method treatment or prevent the disease relevant to inflammation, immunological diseases, infection and cancer and disease.
Compound of the present invention and compositions can with there is the compound of associated uses and compositions coupling thus prevention and therapy object disease or disease, as inflammatory or autoimmune disease, disease and disease, comprise inflammatory bowel, rheumatoid arthritis, osteoarthritis, psoriatic arthritis, polyarthritis, multiple sclerosis, anaphylactic disease, psoriasis, allergic dermatitis and asthma, and those condition of illness as mentioned above.
Such as, in treatment or prevention of inflammation or autoimmune or the relevant bone lesion of such as arthritis, the compounds of this invention and compositions can with antiinflammatory or analgesic coupling, such as opiate agonist, lipoxidase inhibitor, as 5-lipoxygenase, inhibitors of cyclooxygenases, as COX-2 inhibitors, interleukin inhibitors, as interleukin-1 inhibitor, nmda antagonist, nitric oxide inhibitor or nitric oxide synthetic inhibitor, non-carrier antiinflammatory or cytokine suppress antiinflammatory, such as with such as acetaminophen, aspirin, codeine, fentanyl, ibuprofen, indomethacin, ketorolac, morphine, naproxen, phenacetin, piroxicam, steroid analgesics, sufentanil, Su Lin acid, the compound coupling of tenidap etc.Similarly, compound of the present invention and compositions can with analgesics listed above; Synergist as caffeine, H2 antagonist (such as, ranitidine), simethicone, aluminium hydroxide or magnesium; Decongestant, as phyenlephrinium, phenylpropanolamine, pseudoephedrine, oxymetazoline, epinephrine, naphazoline, xylometazoline, propylhexedrine, or SN522; Antitussive medicament as codeine, dihydrocodeinone, Ethanedisulfonate, carbetapentane citrate, or dextromethorphan; Diuretic; Use together with calmness or non-sedative antihistamine agent.
Similarly, compound of the present invention and compositions can with the treatments for disease or disease, and prevention, the other drug coupling suppressing or improve, for above-mentioned disease or disease, compound of the present invention and compositions are useful.These other drugs with conventional use amount by certain approach, simultaneously or in a sequence can be used with compound of the present invention or compositions.When compound of the present invention or compositions and one or more other medicines use simultaneously, the pharmaceutical composition also comprising this other drug except compound of the present invention or compositions is preferred.Therefore, pharmaceutical composition of the present invention comprises except compound of the present invention or compositions, also comprises one or more other active component or therapeutic agent those.Can include, but are not limited to the example of compound of the present invention or compositions or administration or the other treatment agent of coupling in same pharmaceutical composition respectively: (a) VLA-4 antagonist, (b) corticosteroid, such as beclometasone, methyl meticortelone, betamethasone, prednisone, meticortelone (prenisolone), dexamethasone, fluticasone, hydrocortisone, budesonide, triamcinolone, salmaterol, salmaterol, albuterol, formetorex, (c) immunosuppressant as ciclosporin (ciclosporin A, ), tacrolimus (FK-506, ), rapamycin (sirolimus, ), expelling pathogens by strengthening vital QI is for Buddhist nun with other FK-506 type immunosuppressant, and mycophenolate, such as, mycophenolate (d) antihistaminic (H1-histamine antagonist), as brompheniramine, chlorphenamine, dichloro pheniramine, triprolidine, clemastine, diphenhydramine, diphenylpyraline, tripelennamine, hydroxyzine, methdilazine, promethazine, alimemazine, azatadine, Cyproheptadine, antazoline, pheniramine, pyrimidinamine, astemizole, terfenadine, loratadine, cetirizine, fexofenadine, decarboxylation loratadine etc., (e) non-steroidal antasthmatic (such as, terbutaline, orciprenaline, fenoterol, isoetarine, albuterol, bitolterol and pirbuterol), theophylline, sodium cromoglicate, atropine, ipratropium bromide, leukotriene antagonist (such as, zafirlukast, montelukast, pranlukast, iralukast, pobilukast and SKB-106,203), inhibitors of leukotriene biosynthesis (zileuton, Bay-1005), (f) NSAID (non-steroidal anti-inflammatory drug) (NSAIDS), such as propanoic derivatives (such as alminoprofen, Benoxaprofen, bucloxic acid, carprofen, fenbufen, fenoprofen, fluprofen, flurbiprofen, ibuprofen, indoprofen, ketoprofen, miroprofen, naproxen, oxaprozin, pirprofen, pranoprofen, suprofen, tiaprofenic acid and tioxaprofen), acetogenin (such as, indomethacin, acemetacin, alclofenac, clidanac, diclofenac, fenclofenac, fenclozic acid, fentiazac, furofenac, ibufenac, Isoxepac, product acid (oxpinac) difficult to understand, sulindac, tiopinac, tolmetin, zidometacin and zomepirac), fenamic acid derivative is (as flufenamic acid, meclofenamic acid, mefenamic acid, niflumic acid and tolfenamic acid), biphenylcarboxylic acid derivatives (such as, diflunisal and flufenisal), former times health class (such as, isoxicam, piroxicam, sudoxicam and tenoxicam), salicylate (such as, aspirin and sulfasalazine) and pyrazolone is (such as, azapropazone, benzene group dragon (bezpiperylon), feprazone, mofebutazone, oxyphenbutazone and Phenylbutazone), g () COX-2 (COX-2) inhibitor is as celecoxib and rofecoxib (h) phosphodiesterase IN type (PDE IV) inhibitor, i () gold compound is as auranofin and aurothioglucose, (j) Embrel (k) antibody therapy, as Mermithidae dragon (orthoclone) (OKT3) difficult to understand, daclizumab basiliximab and infliximab adalimumab usury monoclonal antibody rituximab tower Xidan resists (l) chemokine receptors, especially CCR5, CXCR2, CXCR3, CCR2, CCR3, CCR4, CCR7, CX 3other antagonist of CRI and CXCR6, m () lubricant or softening agent, as vaseline and lanoline, (n) keratolytic agent (such as, tazarotene), (o) vitamin D 3derivant, as: calcipotriene or calcipotriol (p) PUVA, (q) dithranol (r) etretinate with isotretinoin and (s) agent for treatment of multiple sclerosis, as interferon beta-1 β interferon azathioprine acetic acid copaxone glucocorticoid (such as, prednisolone) and cyclophosphamide, t () DMARDS is as methotrexate, (u) other compound, such as 5-aminosalicylic acid and prodrug thereof, oxychloroquine, Beracilline, antimetabolite, as azathioprine, Ismipur and methotrexate, DNA synthetic inhibitor, if hydroxyurea and microtubule chaff interference are if colchicine and proteasome inhibitor are as bortezomib the weight ratio of the compounds of this invention and the second active component can change, and depends on the effective dose of each composition.Usually, respective effective dose is adopted.Therefore, such as, when compound of the present invention and NSAID coupling, the weight ratio of compound of the present invention and NSAID is generally about 1000:1 to about 1:1000, and preferably about 200:1 is to about 1:200.The combination of compound of the present invention and other active component usually also in above-mentioned scope, but in each case, should use each active component of effective dose
I. embodiment
There is provided following examples for illustrating, but be not used in restriction claimed invention.
The reagent below used and solvent can available from commercial sources, as Aldrich Chemical company (Aldrich Chemical Co., Milwaukee, the state of Wisconsin, USA).Adopt Varian Mercury (Varian Mercury) 400MHz NMR spectrogrph record 1H-NMR spectrum.Relative TMS provides important peak, and tabulates in order: and multiplicity (s, unimodal; D, bimodal; T, three peaks; Q, four peaks; M, multiplet) and proton number.Mass spectral results is reported as mass-to-charge ratio, is the relative abundance (in bracket) of each ion subsequently.In table, for M+H (or as described in the M-H) ion comprising most common atomic isotopes reports single m/e value.Under all situations, isotopic pattern corresponds to the structural formula expected.Hewlett-Packard MSD Electrospray Mass Spectrometry is implemented electron spray ionisation (ESI) mass spectral analysis, adopts and be furnished with Agilent Zorbax SB-C18,2.1X50 millimeter, the HP1100HPLC of 5 μ posts is used for sample presentation.Usually, analyze thing and be dissolved in methanol, concentration is 0.1 mg/ml, and get 1 microlitre and together inject mass spectrum with transmission solvent, mass spectrum scans from 100 to 1500 dalton.All compounds can just ESI pattern analyzed, and adopt acetonitrile/water and 1% formic acid as transmission solvent.The compound below provided also can be analyzed with negative ESI pattern, adopts the 2mM NH in acetonitrile/water 4oAc is as transmission system.
Below abbreviation is used in embodiment and whole description of the invention: HPLC high pressure liquid chromatography; DMF, dimethyl formamide; TFA, trifluoroacetic acid; THF, oxolane; EtOAc, ethyl acetate; BOC 2o, Bis(tert-butoxycarbonyl)oxide or BOC acid anhydride; HPLC, high pressure liquid chromatography; DIPEA, diisopropylethylamine; HBTU, O-(benzotriazole-1-base)-N, N, N ', N '-tetramethylurea hexafluorophosphate; Dppf, 1,1'-bis-(diphenylphosphino) ferrocene; Pd 2(dba) 3, three (dibenzalacetone) two palladium (0); DIPEA, diisopropylethylamine; DMP, dimethyl phthalate; Me, methyl; Et ethyl; DCM, dichloromethane.
Compound in the scope of the invention can synthesize as described below, uses and well known to a person skilled in the art various reaction.Those of skill in the art also will appreciate that, other method can be used for synthesizing target compound of the present invention, although and the method for this paper described in main body is not exhaustive, really for interested compound provides extensive being suitable for and practical route.
Claimed some molecule of this patent can be different enantiomer and diastereomeric form exist, whole such variant of these compounds is all required protection.
Detailed description herein for the synthesis of the experimental arrangement of key compound causes the physical data and the structure relevant to them obtained by characterizing them to describe the molecule described.
Those skilled in the art also will recognize, in vitochemical standard test (work up) program, often use bronsted lowry acids and bases bronsted lowry.In the experimental arrangement described in this patent, sometimes produce the salt of parent compound, if they have necessary intrinsic acidity or basicity.
Embodiment 1
The synthesis of 1-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl]-3-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl] pyrrolidin-2-one
A) under room temperature under nitrogen, by nitronium tetrafluoroborate (Nitronium tetrafluoroborate) (110mg, 0.84mmol) join in the solution of the anhydrous acetonitrile (5.0mL) of 1-(4-fluorophenyl)-5-methyl isophthalic acid H-pyrazoles (120mg, 0.70mmol).Stir after 12 hours, vacuum concentrated mixture also passes through flash chromatography (SiO2,20%EtOAc/ hexane) purification thus obtains product (53mg, 0.24mmol, 34%), is water white oil.
B) containing 1-(4-the fluorophenyl)-5-methyl-4-nitro-pyrazole (50mg that the step a in MeOH (5mL) obtains, 0.23mmol) with 10%Pd/C (10mg, heavy-walled glass flask 20wt%) is installed to Pa Er (Parr) instrument, and at 45psi stirring under hydrogen.After 1h, filtering reactant mixture vacuum concentrated filtrate by Celite pad thus obtain product (240mg, 1.2mmol, 99%), is orange oil.Roughage does not need to be further purified for next step.
C) under nitrogen, by trimethyl aluminium (0.25mL, 2M, in toluene, 0.50mmol) slowly join 1-(4-fluorophenyl)-5-methylpyrazole-4-amine (47mg, 0.25mmol) and 3-[5-methyl-3-(trifluoromethyl)-1 that step b obtains, 2,4-triazol-1-yl] in the solution of oxolane-2-ketone (58mg, 0.25mmol) in 1,2-dichloroethanes (5mL).Mixture stirred at room temperature 20 minutes, afterwards by adding the careful cancellation reaction of 1 –, 2 1N HCl.After bubbling is calmed down, dilute viscous mixture with other 1N HCl and use CH 2cl 2(3 × 20mL) extracts.The dry organic extract merged, filters and vacuum concentration over magnesium sulfate.Roughage does not need to be further purified for next step.
D) to step c obtain thick alcohol intermediate (assuming that 0.25mmol) and triethylamine (0.14mL, 1.0mmol) at CH 2cl 2(3mL) mesyl chloride (0.040mL, 0.50mmol) is slowly added in the solution in.Stirring at room temperature reactant mixture 15 minutes, uses CH afterwards 2cl 2dilute and wash with water.Be separated organic layer, dry over magnesium sulfate, filter and vacuum concentration.Thick yellow oil does not need to be further purified for next step.
E), under room temperature, in the thick mesylate intermediate (assuming that 0.25mmol) that the steps d in oxolane (2mL) obtains, sodium hydride (40mg, 60%, in mineral oil, 1.0mmol) is once added.Stir after 30 minutes, by adding saturated NH 4the cancellation of Cl aqueous solution is reacted and uses CH 2cl 2(2 × 20mL) extracts.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.Obtaining title compound (35mg, 0.086mmol, 34%, through three steps) by reversed-phase HPLC (C18 post, containing the acetonitrile-water of 0.1%TFA as eluent) purification of crude residue, is white solid. 1h NMR (400MHz, CDCl 3) δ 7.65 (s, 1H) 7.42 (dd, J=9.0,5.1Hz, 2H), 7.18 (dd, J=8.8,8.0Hz, 2H), 5.11 (dd, J=8.6,6.4Hz, 1H), 4.07 (ddd, J=9.8,8.6,5.8Hz, 1H), 3.92 (ddd, J=9.8,7.8,5.8Hz, 1H), 2.80 – 2.88 (m, 2H), 2.66 (s, 3H), 2.22 (s, 3H) MS:(ES) m/z calculates C 18h 16f 4n 6o [M+H] +409.1, actual measurement 409.1.
Embodiment 2
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl] pyrrolidin-2-one
A) under room temperature under nitrogen, by trimethyl aluminium (0.16mL, 2M, in toluene, 0.32mmol) slowly join 1-(4-fluorophenyl)-5-methylpyrazole-4-amine (40mg in 1,2-dichloroethanes (2mL), 0.21mmol) with 3-[5-methyl-3-(trifluoromethyl)-1,2,4-triazol-1-yl] oxolane-2-ketone (58mg, 0.25mmol) solution in.Stir the mixture 30 minutes, afterwards by adding several careful cancellation reactions of 1N HCl.After bubbling is calmed down, dilute viscous mixture with other 1N HCl and use CH 2cl 2(2 × 20mL) extracts.The dry organic extract merged, filters and vacuum concentration over magnesium sulfate.Roughage does not need to be further purified for next step.
B) to step a obtain thick alcohol intermediate (assuming that 0.21mmol) and triethylamine (0.10mL, 0.63mmol) at CH 2cl 2(3mL) mesyl chloride (0.025mL, 0.32mmol) is slowly added in the solution in.Stirring at room temperature reactant mixture 15 minutes, uses CH afterwards 2cl 2dilute and wash with water.Be separated organic layer, dry over magnesium sulfate, filter and vacuum concentration.Roughage does not need to be further purified for next step.
C), under room temperature, in the thick mesylate intermediate (assuming that 0.21mmol) that the step b in oxolane (2mL) obtains, sodium hydride (40mg, 60%, in mineral oil, 1.0mmol) is once added.Stir after 30 minutes, by adding saturated NH 4the cancellation of Cl aqueous solution is reacted and uses CH 2cl 2(2 × 20mL) extracts.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.Obtaining title compound (20mg, 0.045mmol, 22%, through three steps) by reversed-phase HPLC (C18 post, containing the acetonitrile-water of 0.1%TFA as eluent) purification of crude residue, is white solid. 1h NMR (400MHz, CDCl 3) δ 7.66 (s, 1H), 7.42 (dd, J=8.8,4.8Hz, 2H), 7.18 (dd, J=8.4,8.4Hz, 2H), 5.06 (dd, J=9.1,6.0Hz, 1H), 4.05 (ddd, J=9.6,8.4,5.3Hz, 1H), 3.90 (ddd, J=9.6,8.0,5.5Hz, 1H), 2.85 (dddd, J=13.6,8.0,5.6,5.6Hz, 1H), 2.75 (dddd, J=13.6,8.0,8.0,5.2Hz, 1H), 2.42 (s, 3H), 2.21 (s, 3H); MS:(ES) m/z calculates C 19h 16clF 4n 5o [M+H] +442.1, actual measurement 442.1.
Embodiment 3
The synthesis of 1-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) under room temperature under nitrogen, by trimethyl aluminium (0.26mL, 2M, in toluene, 0.52mmol) slowly join 1, in 1-(4-fluorophenyl)-5-methylpyrazole-4-amine (50mg, 0.26mmol) in 2-dichloroethanes (2mL) and the solution of α-bromo-gamma-butyrolacton (85mg, 0.52mmol).Stir the mixture 1 hour, afterwards by adding several careful cancellation reactions of 1N HCl.After bubbling is calmed down, dilute viscous mixture with other 1N HCl and use CH 2cl 2(2 × 20mL) extracts.The dry organic extract merged, filters and vacuum concentration over magnesium sulfate.Roughage does not need to be further purified for next step.
B) to step a obtain thick alcohol intermediate (assuming that 0.26mmol) and triethylamine (0.11mL, 0.78mmol) at CH 2cl 2(3mL) mesyl chloride (0.030mL, 0.39mmol) is slowly added in the solution in.Stirring at room temperature reactant mixture 15 minutes, uses CH afterwards 2cl 2dilute and wash with water.Be separated organic layer, dry over magnesium sulfate, filter and vacuum concentration.Roughage does not need to be further purified for next step.
C), under room temperature, in the thick mesylate intermediate (assuming that 0.61mmol) that the step b in oxolane (2mL) obtains, sodium hydride (40mg, 60%, in mineral oil, 1.0mmol) is once added.Stir after 30 minutes, by adding saturated NH 4the cancellation of Cl aqueous solution is reacted and uses CH 2cl 2(2 × 20mL) extracts.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.Roughage does not need to be further purified for next step.
D) by thick bromide intermediate (assuming that 0.26mmol), the 2-methyl-4-trifluoromethyl imidazoles (40mg of step c acquisition, 0.26mmol) stir 12 hours at 65 DEG C with the mixture of potassium carbonate (40mg, 0.29mmol) in DMF (2mL).Mixture is cooled to room temperature, dilutes with EtOAc (20mL) and washes with water.With EtOAc (1 × 10mL) and CH 2cl 2(1 × 10mL) anti-water lift layer.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.Being obtained the trifluoroacetate (28mg, 0.0054mmol, 21%, through four steps) of title compound by reversed-phase HPLC (C18 post, containing the acetonitrile-water of 0.1%TFA as eluent) purification of crude material, is white solid. 1h NMR (400MHz, CDCl 3) δ 7.69 (s, 1H), 7.43 (dd, J=8.8,4.8Hz, 2H), 7.30 – 7.28 (m, 1H), 7.21 (dd, J=8.0,8.0Hz, 2H), 5.07 (dd, J=10.4,8.8Hz, 1H), 3.98 (ddd, J=10.0,10.0,6.8Hz, 1H), 3.89 (ddd, J=10.8,9.2,2.0Hz, 1H), 2.94 – 2.88 (m, 1H), 2.61 (s, 3H), 2.48 – 2.39 (m, 1H), 2.27 (s, 3H); MS:(ES) m/z calculates C 19h 17f 4n 5o [M+H] +408.1, actual measurement 408.1.
Embodiment 4
The synthesis of 1-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] piperidines-2-ketone
Adopt the process described as embodiment 3 to prepare title compound, replace α-bromo-gamma-butyrolacton in step 3a 3-bromine Pentamethylene oxide .-2-ketone. 1h NMR (400MHz, CDCl 3) δ 7.66 (s, 1H), 7.40 (dd, J=9.2,4.8Hz, 2H), 7.29 – 7.26 (m, 1H), 7.19 (t, J=8.0Hz, 2H), 4.89 (dd, J=11.2,5.6Hz, 1H), 3.88 (J=12.4,10.4,4.8Hz, 1H), 3.80 – 3.73 (m, 1H), 2.60 (s, 3H) .2.60 – 2.53 (m, 1H), 2.40 – 2.23 (m, 3H), 2.15 (s, 3H); MS:(ES) m/z calculates C 20h 19f 4n 5o [M+H] +422.2, actual measurement 422.1.
Embodiment 5
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl) pyrazoles-4-base] pyrrolidin-2-one
A), under air at room temperature, CH is stirred 2cl 2(100mL) the 4-flurophenyl boronic acid (5.02g in, 35.4mmol), 4-nitro-1H-pyrazoles (2.00g, 17.7mmol), the solution 12 hours of copper acetate (3.50g, 19.5mmol) and pyridine (7.00mL, 88.5mmol).Then by Celite pad filtering mixt, vacuum concentrated filtrate.By flash chromatography (SiO 2, 30%EtOAc/ hexane) and purification of crude residue thus obtain product is white solid.
B) 1-(4-the fluorophenyl)-4-nitro-pyrazole (assuming that 17.7mmol) obtained containing the step a in EtOH (50mL) and EtOAc (10mL) and the heavy-walled glass flask of 10%Pd/C (0.30g) are installed to Pa Er (Parr) instrument, and at 40psi stirring under hydrogen.After 1h, filter reactant mixture vacuum concentrated filtrate thus obtain product by Celite pad, being red solid (4.0g, 22.6mmol, 63%, through two steps), is orange oil.Product does not need to be further purified and is used.
C) under room temperature, to CH 2cl 2(30mL) 2-[the chloro-5-methyl of 4--3-(trifluoromethyl) the pyrazol-1-yl]-4-hydroxy-butyric acid (0.77g in, 2.7mmol) and N, N-diisopropylethylamine (1.9mL, trim,ethylchlorosilane (0.85mL, 6.8mmol) is added in solution 11mmol).Stir the mixture 5 minutes, add mesyl chloride (0.52mL, 6.8mL) afterwards.After stirring 10 minutes again, adding is respectively the sodium bicarbonate (0.45g, 5.4mmol) of solid and 1-(4-fluorophenyl) pyrazoles-4-amine (0.32g, 1.8mmol) of step a acquisition.Mixture stirred at room temperature 12h.React by adding 1N HCl (30mL) cancellation and use CH 2cl 2(1 × 50mL) extracts.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.By flash chromatography (SiO 2, 20% – 50%EtOAc/ hexane) and purification of crude material obtains product, be orange oil (140mg, 0.31mmol, 18%).
D) under a nitrogen diethylazodicarboxylate (75 μ L, 0.47mmol) is slowly joined in the triphenylphosphine (124mg, 0.47mmol) in oxolane (2mL).Stirring at room temperature yellow solution, adds oxolane (3mL) solution of the alcohol intermediate (140mg, 0.30mmol) that step c obtains afterwards.After stirred overnight at room temperature, react by adding saturated sodium bicarbonate aqueous solution cancellation and use CH 2cl 2(2 × 20mL) extracts mixture.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.By flash chromatography (SiO 2, 20 – 50%EtOAc/ hexanes) and reversed-phase HPLC (C18 post, containing the acetonitrile-water of 0.1%TFA as eluent) purification of crude material thus obtain title compound (10mg, 0.023mmol, 8%), be white solid. 1h NMR (400MHz, CDCl 3) δ 8.46 (s, 1H), 7.74 (s, 1H), 7.64 (dd, J=9.2,4.8Hz, 2H), 7.15 (dd, J=8.8,8.0Hz, 2H), 5.12 (dd, J=9.3,7.5Hz, 1H), 4.12 (ddd, J=9.2,9.2,3.9Hz, 1H), 3.97 – 3.86 (m, 1H), 3.10 (dddd, J=14.0,8.8,6.8,0.4Hz, 1H), 2.77 (dddd, J=13.2,9.6,7.6,3.6Hz, 1H), 2.44 (s, 3H); MS:(ES) m/z calculates C 18h 14clF 4n 5o [M+H] +428.1, actual measurement 428.1.
Embodiment 6
The synthesis of 1-[1-(4-fluorophenyl) pyrazoles-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) under room temperature under nitrogen, by trimethyl aluminium (1.4mL, 2M, in toluene, 2.8mmol) slowly join 1, in the solution of 1-(4-fluorophenyl) pyrazoles-4-amine (0.24g, 1.4mmol) and 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone (0.32g, 1.4mmol) in 2-dichloroethanes (2mL).Stir the mixture 30 minutes, afterwards by adding several careful cancellation reactions of 1NHCl.After bubbling is calmed down, dilute viscous mixture with other 1N HCl and use CH 2cl 2(3 × 20mL) extracts.The dry organic extract merged, filters and vacuum concentration over magnesium sulfate.Roughage does not need to be further purified for next step.
B) to step a obtain thick alcohol intermediate (89mg 0.21mmol) and triethylamine (90 μ L, 0.65mmol) at CH 2cl 2(2mL) mesyl chloride (25 μ L, 0.31mmol) is slowly added in the solution in.Stirring at room temperature reactant mixture 1 hour, uses CH afterwards 2cl 2dilute and wash with water.Be separated organic layer, dry over magnesium sulfate, filter and vacuum concentration.Roughage does not need to be further purified for next step.
C), under room temperature, in the thick mesylate intermediate (assuming that 0.21mmol) that the step b in oxolane (2mL) obtains, sodium hydride (30mg, 60%, in mineral oil, 0.65mmol) is once added.Stir after 30 minutes, by adding saturated NH 4the cancellation of Cl aqueous solution is reacted and uses CH 2cl 2(2 × 20mL) extracts.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.Obtaining the trifluoroacetate (24mg, 0.047mmol, 20%, through two steps) of title compound by reversed-phase HPLC (C18 post, containing the acetonitrile-water of 0.1%TFA as eluent) purification of crude material, is white solid. 1h NMR (400MHz, CDCl 3) δ 8.53 (s, 1H), 7.76 (s, 1H), 7.66 (dd, J=9.0,4.5Hz, 2H), 7.27 – 7.25 (m, 2H), 7.15 (dd, J=9.2,8.4Hz, 2H), 5.07 (dd, J=9.5,9.5Hz, 1H), 4.05 – 3.91 (m, 1H), 2.97 (dddd, J=13.6,8.4,6.8,2.0Hz, 1H), 2.59 (s, 3H), 2.42 (dddd, J=13.6,9.6,3.6,3.6Hz, 1H); MS:(ES) m/z calculates C 18h 15clF 4n 5o [M+H] +394.1, actual measurement 394.1.
Embodiment 7
The synthesis of 1-[1-(4-fluorophenyl) pyrazoles-4-base]-3-[5-methyl-3-(trifluoromethyl) pyrazol-1-yl] pyrrolidin-2-one
Adopt the process described as embodiment 6 to prepare title compound, in step 6a, replace 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone with 3-[5-methyl-3-(trifluoromethyl) pyrazol-1-yl] oxolane-2-ketone. 1hNMR (400MHz, CDCl 3) δ 8.46 (s, 1H), 7.74 (s, 1H), 7.64 (dd, J=8.8,4.4Hz, 2H), 7.14 (dd, J=9.2,8.4Hz, 2H), 6.35 (s, 1H), 5.119 (dd, J=8.8,4.4Hz, 1H), 4.13 (ddd, J=9.2,9.2,4.0Hz, 1H), 3.90 (ddd, J=9.6,8.0,6.8Hz, 1H), 3.10 (dddd, J=13.2,8.8,7.2,7.2Hz, 1H), 2.78 (dddd, J=13.2,9.2,8.0,3.6Hz, 1H), 2.46 (s, 3H); MS:(ES) m/z calculates C 19h 15f 4n 5o [M+H] +394.1, actual measurement 394.1.
Embodiment 8
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl) pyrazoles-4-base] piperidines-2-ketone
Adopt the process described as embodiment 6 to prepare title compound, in step 6a, replace 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone with 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl] Pentamethylene oxide .-2-ketone. 1hNMR (400MHz, CDCl 3) δ 8.40 (s, 1H), 7.75 (s, 1H), 7.61 (dd, J=9.0,4.5Hz, 2H), 7.12 (dd, J=8.0,8.0Hz, 2H), 4.92 (dd, J=11.2,5.8Hz, 1H), 3.98 – 3.85 (m, 2H), 2.88 – 2.72 (m, 1H), 2.46 – 2.35 (m, 1H), 2.38 (s, 3H), 2.23 – 2.10 (m, 2H); MS:(ES) m/z calculates C 19h 16clF 4n 5o [M+H] +442.1, actual measurement 442.1.
Embodiment 9
The synthesis of 1-[1-(4-fluorophenyl) pyrazoles-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] piperidines-2-ketone
Adopt the process described as embodiment 6 to prepare title compound, in step 6a, replace 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone with 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] Pentamethylene oxide .-2-ketone. 1hNMR (400MHz, CDCl 3) δ 8.54 (s, 1H), 7.76 (s, 1H), 7.63 (dd, J=8.8,4.8Hz, 2H), 7.25 – 7.22 (m, 1H), 7.15 (dd, J=8.0,8.0Hz, 2H), 4.87 (dd, J=11.5,5.7Hz, 1H), 4.00 – 3.88 (m, 2H), 2.61 (s, 3H), 2.56 – 2.50 (m, 1H), 2.46 – 2.37 (m, 1H), 2.37 – 2.20 (m, 2H); MS:(ES) m/z calculates C 19h 17f 4n 5o [M+H] +408.1, actual measurement 408.1.
Embodiment 10
The synthesis of 1-[1-(4-fluorophenyl) pyrazoles-4-base]-3-[5-methyl-3-(trifluoromethyl) pyrazol-1-yl] piperidines-2-ketone
Adopt the process described as embodiment 6 to prepare title compound, in step 6a, replace 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone with 3-[5-methyl-3-(trifluoromethyl) pyrazol-1-yl] Pentamethylene oxide .-2-ketone. 1hNMR (400MHz, CDCl 3) δ 8.55 (s, 1H), 7.74 (s, 1H), 7.61 (ddd, J=9.2,4.8,2.0Hz, 2H), 7.12 (dd, J=9.2,8.0Hz, 2H), 6.34 (s, 1H), 4.93 (dd, J=11.2,5.7Hz, 1H), 3.99 – 3.84 (m, 2H), 2.81 (dddd, J=13.6,11.6,10.4,2.8Hz, 1H), 2.46 – 2.35 (m, 2H), 2.42 (s, 3H), 2.17 (dddd, J=13.6,10.4,6.8,2.8Hz, 1H); MS:(ES) m/z calculates C 19h 17f 4n 5o [M+H] +408.1, actual measurement 408.1.
Embodiment 11
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[5-ethyl-1-(4-fluorophenyl) pyrazoles-4-base] pyrrolidin-2-one
A) at the mixture 1 day of 110 DEG C of heating 2-butanone (1.10g, 15.3mmol) and DMF dimethyl-acetal (2.20g, 18.3mmol).After cooling, thick reactant mixture is directly used in next step.
B) at 85 DEG C, the solution of 1-(dimethylamino) penta-1-alkene-3-ketone that the 4-fluorophenylhydrazine hydrochloride (2.50g, 15.3mmol) in heating oxolane (5mL) and step a obtain 1 day.After cool to room temperature, CH 2cl 2(50mL) dilution mixture thing washing with water.Dry organic layer over magnesium sulfate, filters and vacuum concentration.By flash chromatography (SiO 2, 0 – 20%EtOAc/ hexane) and purification of crude material obtains product (1.1g, 5.8mmol, 37%), is reddish oil.
C) under room temperature under nitrogen, by nitronium tetrafluoroborate (500mg, 2.3mmol) join in the solution of the anhydrous acetonitrile (10mL) of 5-ethyl-1-(4-fluorophenyl) pyrazoles (420mg, 3.2mmol) that step b obtains.Stir after 12 hours, vacuum concentrated mixture also passes through flash chromatography (SiO2,50%EtOAc/ hexane) purification thus obtains product (53mg, 0.023mmol, 9%), is yellow oil.
D) containing the product (53mg that the step c in MeOH (1mL) and EtOAc (2mL) obtains, 0.023mmol) with 10%Pd/C (11mg, heavy-walled glass flask 20wt%) is installed to Pa Er (Parr) instrument, and at 45psi stirring under hydrogen.After 1.5h, filtering reactant mixture vacuum concentrated filtrate by Celite pad thus obtain product (45mg, 0.023mmol, 99%), is yellow oil.Roughage does not need to be further purified for next step.
E) under room temperature under nitrogen, by trimethyl aluminium (0.2mL, 2M, in toluene, 0.39mmol) slowly join 5-ethyl-1-(4-fluorophenyl) pyrazoles-4-amine (45mg that steps d obtains, 0.023mmol) with in 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl] solution of oxolane-2-ketone (76mg, 0.28mmol) in 1,2-dichloroethanes (3mL).Mixture stirred at room temperature 30 minutes, afterwards by adding several careful cancellation reactions of 1N HCl.After bubbling is calmed down, dilute viscous mixture with more 1N HCl and use CH 2cl 2(3 × 10mL) extracts.The dry organic extract merged, filters and vacuum concentration over magnesium sulfate.Roughage does not need to be further purified for next step.
F) to step e obtain thick alcohol intermediate (assuming that 0.23mmol) and triethylamine (110 μ L, 0.78mmol) at CH 2cl 2(2mL) mesyl chloride (25 μ L, 0.31mmol) is slowly added in the solution in.Stirring at room temperature reactant mixture 1 hour, uses CH afterwards 2cl 2dilute and wash with water.Be separated organic layer, dry over magnesium sulfate, filter and vacuum concentration.Roughage does not need to be further purified for next step.
G), under room temperature, in the thick mesylate intermediate (assuming that 0.23mmol) that the step f in oxolane (2mL) obtains, sodium hydride (30mg, 60%, in mineral oil, 0.65mmol) is once added.Stir after 30 minutes, by adding saturated NH 4the cancellation of Cl aqueous solution is reacted and uses CH 2cl 2(2 × 20mL) extracts.Merge organic layer, dry over magnesium sulfate, filter and vacuum concentration.Obtaining title compound (51mg, 0.11mmol, 48%, through three steps) by reversed-phase HPLC (C18 post, containing the acetonitrile-water of 0.1%TFA as eluent) purification of crude material, is white solid. 1h NMR (400MHz, CDCl 3) δ 7.60 (s, 1H), 7.40 (dd, J=8.9,4.8Hz, 2H), 7.17 (dd, J=8.4,8.4Hz, 2H), 5.04 (dd, J=9.1,5.8Hz, 1H), 4.06 (ddd, J=9.8,8.4,5.4Hz, 1H), 3.87 (ddd, J=9.7,8.2,5.3Hz, 1H), 2.86 (dddd, J=14.0,84,8.4,6.0Hz, 1H), 2.74 (dddd, J=14.4,9.2,8.8,5.6Hz, 1H), 2.65 (dddd, J=15.2,7.6,7.6,1.2Hz, 2H), 2.43 (s, 3H) .0.97 (t, J=7.6Hz, 3H); MS:(ES) m/z calculates C 20h 18clF 4n 5o [M+H] +456.1, actual measurement 456.1.
Embodiment 12
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-isopropyl-pyrazoles-4-base] pyrrolidin-2-one
Adopt the process described as embodiment 2 to prepare title compound, in step 2a, replace 1-(4-fluorophenyl)-5-methyl pyrazole-4-amine with 1-(4-fluorophenyl)-5-isopropyl-pyrazoles-4-amine. 1h NMR (400MHz, CDCl 3) δ 7.55 (s, 1H), 7.38 (dd, J=8.9,4.8Hz, 2H), 7.18 (dd, J=8.5,8.5Hz, 2H), 5.04 (dd, J=9.3,5.9Hz, 1H), 4.04 (ddd, J=10.0,8.8,5.2Hz, 1H), 3.82 (ddd, J=10.0,8.4,5.6Hz, 1H), 3.01 – 2.92 (m, 1H), 2.92 – 2.84 (m, 1H), 2.80 – 2.69 (m, 1H), 2.42 (s, 3H), 1.21 (d, J=6.8,3H), 1.11 (d, J=6.8,3H); MS:(ES) m/z calculates C 21h 20clF 4n 5o [M+H] +470.1, actual measurement 470.1.
Embodiment 13
The synthesis of 1-[the 5-tert-butyl group-1-(4-fluorophenyl) pyrazoles-4-base]-3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl] pyrrolidin-2-one
A) at 110 DEG C, the mixture of pivaloyl methyl acetate (5.80g, 36.7mmol) and DMF dimethyl-acetal (5.24g, 44.0mmol) is heated 1 day.After cooling, vacuum concentration reactant mixture thus remove volatile matter, roughage is directly used in next step.
B) the 4-fluorophenyl hydrazine hydrochloride (5.97g in 85 DEG C of heating oxolane (15mL), the solution of 2-(dimethylamino methene)-4, the 4-dimethyl-3-oxopentanoic (assuming that 36.7mmol) 36.7mmol) obtained with step a 1 hour.After cool to room temperature, use CH 2cl 2(50mL) dilution mixture thing washing with water.Dry organic layer over magnesium sulfate, filters and vacuum concentration.By flash chromatography (SiO 2, 0 – 20%EtOAc/ hexane) and purification of crude material obtains product (5.0g, 18.1mmol, 50% through two steps), is reddish oil.
C) at 80 DEG C, the 5-tert-butyl group-1-(4-fluorophenyl) pyrazoles-4-carboxylate methyl ester (5.00g that step b in heated and stirred dioxane (20mL) and water (20mL) obtains, 18.1mmol) and the biphasic solution 1.5h of lithium hydroxide monohydrate (2.77g, 66.0mmol).After cooling, use CH with 1N HCl dilution mixture thing 2cl 2(1 × 100mL) extracts.Dry organic layer over magnesium sulfate, filters and vacuum concentration.Thick brown solid does not need to be further purified and is used.
D), under stirring, the solution of the 5-tert-butyl group-1-(4-fluorophenyl) pyrazoles-4-carboxylic acid (0.67g, 2.6mmol) that the step c in heating thionyl chloride (2.0mL) obtains was to backflow 20 minutes.Reactant mixture is cooled to room temperature and vacuum concentration.Roughage and toluene (2 × 10mL) azeotropic also place several hours under a high vacuum, afterwards for next step.
E) in acetone (15mL) solution of the 5-tert-butyl group-1-(4-fluorophenyl) pyrazoles-4-formyl chloride (assuming that 2.6mmol) of steps d acquisition, add water (2mL) solution of Hydrazoic acid,sodium salt (0.50g, 7.7mmol) fast., there is precipitate thus in room temperature vigorous stirring mixture 5 minutes.Filtering mixt obtains product (0.49g, 1.7mmol), is gray solid.
Toluene (0.5mL) solution of the acid azide intermediate (86mg, 0.030mmol) f) obtained at 110 DEG C of heating steps e 10 minutes, then adds 1N HCl (0.7mL), spends the night at 110 DEG C of heating biphase mixtures.After cooling, extract mixture with chloroform (2 × 10mL).The dry organic layer merged, filters and vacuum concentration over magnesium sulfate.By flash chromatography (SiO 2, 5%MeOH/CH 2cl 2) purification of crude material obtains product (40mg, 0.017mmol, 57%), is brown semi solid.
G) material that step f obtains is used for the process similar to embodiment 2, in step 2a, adopt the 5-tert-butyl group-1-(4-fluorophenyl) pyrazoles-4-amine to replace 1-(4-fluorophenyl)-5-methylpyrazole-4-amine, thus obtain title compound. 1h NMR (400MHz, CDCl 3) δ 7.54 (s, 1H), 7.38 (dd, J=9.2,4.8Hz, 2H), 7.16 (dd, J=8.4,8.4Hz, 2H), 5.09 – 5.00 (m, 1H), 4.08 – 3.99 (m, 1H), 3.83 (dq, J=8.0,8.0,6.0Hz, 1H), 3.04 – 2.87 (m, 1H), 2.80 – 2.67 (m, 1H), 2.42 (s, 3H), 1.17 (s, 9H); MS:(ES) m/z calculates C 22h 22clF 4n 5o [M+H] +484.1, actual measurement 484.1.
Embodiment 14
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-[(E)-1-methyl-prop-1-thiazolinyl] pyrazoles-4-base] pyrrolidin-2-one
A) by process raw materials 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl) the iodo-pyrazoles of-5--4-base] pyrrolidin-2-one of similar embodiment 2,1-(4-fluorophenyl) the iodo-pyrazoles of-5--4-amine is adopted to replace 1-(4-fluorophenyl)-5-methyl pyrazole-4-amine in step 2a.3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl) the iodo-pyrazoles of-5--4-base] pyrrolidin-2-one (90mg in dioxane (5mL) will be comprised, 0.16mmol), (2Z)-2-butylene-2-base three Potassium borofluoride (32mg, 0.20mmol), PdCl 2(dppf) solution of (6.0mg, 0.0080mmol) and aqueous 2M sodium carbonate (0.25mL, 0.49mmol) be heated to 80 DEG C 2 hours.After cool to room temperature, dilute with water reactant mixture also uses CH 2cl 2(2 × 10mL) extracts.The dry organic layer merged, filters and vacuum concentration over magnesium sulfate.By flash chromatography (SiO 2, 20 – 50%EtOAc/ hexanes) and purification of crude material obtains title compound (33mg, 0.070mmol), is pale solid. 1h NMR (400MHz, CDCl 3) δ 7.69 (s, 1H), 7.45 (dd, J=8.9, 4.8Hz, 2H), 7.11 (dd, J=8.0, 8.0Hz, 2H), 5.73 (dddd, J=8.4, 6.8, 6.8, 1.6Hz, 1H), 5.02 (dd, , J=9.2, 6.9Hz, 1H), 3.94 (ddd, , J=9.6, 8.8, 4.8Hz, 1H), 3.76 (ddd, , J=9.6, 7.9, 6.2Hz, 1H), 2.92 (dddd, , J=13.6, 13.6, 8.8, 6.4Hz, 1H), 2.67 (dddd, , J=13.6, 9.2, 8.0, 4.4Hz, 1H), 2.41 (s, 3H), 1.69 (dd, , J=6.8, 1.2Hz, 3H), 1.60 (dd, J=1.2, 1.2Hz, 3H), MS:(ES) m/z calculates C 22h 20clF 4n 5o [M+H] +482.1, actual measurement 482.1.
Embodiment 15
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[5-cyclopropyl-1-(4-fluorophenyl) pyrazoles-4-base] pyrrolidin-2-one
A)-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl) the iodo-pyrazoles of-5--4-base] pyrrolidin-2-one (34mg will to be comprised in toluene (1.5mL), 0.061mmol), cyclopropylboronic acid (7mg, 0.08mmol), acid chloride (1.0mg, 0.003mmol), tricyclohexyl phosphine (2.0mg, 0.006mmol) and the solution of potassium phosphate (45mg, 0.21mmol) be heated to 100 DEG C 1 day.After cool to room temperature, dilute with water reactant mixture also uses CH 2cl 2(2 × 10mL) extracts.The dry organic layer merged, filters and vacuum concentration over magnesium sulfate.Obtaining title compound (1.0mg, 0.002mmol, 3%) by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA as eluent) purification of crude material, is colourless residue. 1h NMR (400MHz, CDCl 3) δ 7.61 (s, 1H), 7.54 (dd, J=9.0, 4.8Hz, 2H), 7.16 (dd, J=9.0, 8.2Hz, 2H), 5.06 (dd, J=9.2, 6.3Hz, 1H), 4.11 (ddd, J=9.6, 8.4, 4.8Hz, 1H), 3.91 (ddd, J=9.6, 8.0, 4.8Hz, 1H), 2.98 (dddd, J=12.0, 9.6, 8.4, 6.4, 6.0Hz, 1H), 2.74 (dddd, J=13.2, 9.2, 8.0, 4.8Hz, 1H), 2.45 (s, 3H), 1.77 (dddd, J=8.4, 8.4, 5.6, 5.6Hz, 1H), 0.78 – 0.64 (m, 2H), 0.43 – 0.30 (m, 2H), MS:(ES) m/z calculates C 21h 18clF 4n 5o [M+H] +468.1, actual measurement 468.1.
Embodiment 16
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-sec-butyl-pyrazoles-4-base] pyrrolidin-2-one
A) product (27mg of the embodiment 14 in MeOH (5mL) will be comprised, 0.056mmol), the heavy-walled glass flask of platinum oxide (25mg, 0.11mmol) and concentrated hydrochloric acid (3) is installed to Pa Er instrument and at 45psi stirring under hydrogen.After 2h, filter reactant mixture and vacuum concentrated filtrate by Celite pad.By flash chromatography (SiO 2, 20 – 50%EtOAc/ hexanes) and purification of crude material obtains title compound (6mg, 0.012mmol, 22%), is the mixture of diastereomer. 1h NMR (400MHz, CDCl 3) δ 7.53 (s, 1H), 7.35 (dd, J=8.9,4.8Hz, 2H), 7.17 (dd, J=8.8,8.2Hz, 2H), 5.02 (dd, J=9.2,5.8Hz, 1H), 4.02 (dddd, J=10.0,9.2,6.0,5.6Hz, 1H), 3.79 (dddd, J=10.0,8.8,5.6Hz, 1H), 2.93 – 2.92 (m, 1H), 2.79 – 2.60 (m, 2H), 2.42 (s, 3H), 1.56 – 1.42 (m, 1H), 1.20 (d, J=7.2Hz, 1H), 1.10 (d, J=7.2Hz, 3H), 0.77 (t, J=7.2Hz, 3H); MS:(ES) m/z calculates C 22h 22clF 4n 5o [M+H] +484.1, actual measurement 484.1.
Embodiment 17
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-propylpyrazol-4-base] pyrrolidin-2-one
A) at the mixture 1 day of 110 DEG C of heating butyryl methyl acetate (5.00g, 34.7mmol) and DMF dimethyl-acetal (5.00g, 41.6mmol).After cooling, vacuum concentration reactant mixture thus remove any volatile matter, roughage is directly used in next step.
B) the 4-fluorophenyl hydrazine hydrochloride (5.64g in 85 DEG C of heating oxolane (25mL), the solution of 2-(dimethylamino methene)-4, the 4-dimethyl-3-oxo-methyl caproate (assuming that 34.7mmol) 34.7mmol) obtained with step a 1 hour.After cool to room temperature, use CH 2cl 2(50mL) dilution mixture thing is also with 1N HCl (1 × 50mL) and saturated NaHCO 3aqueous solution (1 × 50mL) washs.Dry organic layer over magnesium sulfate, filters and vacuum concentration.Roughage is directly used in next step.
C) under agitation 1-(4-the fluorophenyl)-5-propylpyrazol-4-carboxylate methyl ester (assuming that 34.7mmol) of step b acquisition and the biphasic solution 3 hours of lithium hydroxide monohydrate (7.3g, 173mmol) in 80 DEG C of heating dioxane (40mL) and water (20mL).After cooling, adopt 1N HCl acidifying mixture and use CH 2cl 2(2 × 40mL) and EtOAc (2 × 40mL) extract.The dry organic layer merged, filters and vacuum concentration over magnesium sulfate.By flash chromatography (SiO 2, 20 – 50%EtOAc/ hexanes) and purification of crude material thus obtain product (6.65g, 26.5mmol, 76%) is reddish oil.
D) to 1-(4-the fluorophenyl)-5-propylpyrazol-4-carboxylic acid (0.76g that step c obtains, triethylamine (0.47mmol is added in dioxane (8mL) solution 3.1mmol), 3.4mmol) with diphenylphosphoryl azide (0.65mL, 3.1mmol).Then mixture stirred at room temperature 2h is heated to 90 DEG C and stirs 30 minutes.Reaction is cooled to room temperature, adds benzylalcohol (0.63mL, 6.1mmol).Stir at heating blends to 90 DEG C and in this temperature and spend the night.After cooling, wash with water with diethyl ether (50mL) dilution mixture thing.Dry organic layer over magnesium sulfate, filters and vacuum concentration.By flash chromatography (SiO 2, 20 – 50%EtOAc/ hexanes) and purification of crude material obtains product (0.91g, 2.6mmol, 84%), is brown oil.
E) amine (0.91g of the benzyloxycarbonyl group protection that the steps d in MeOH (2mL) and EtOAc (20mL) obtains will be comprised; 2.6mmol), the heavy-walled glass flask of concentrated hydrochloric acid (5) and 10%Pd/C (90mg, 10wt%) is installed to Pa Er instrument and at 45psi stirring under hydrogen.After 3h, filter reactant mixture and vacuum concentrated filtrate by Celite pad. dilute roughage with EtOAc (40mL) and use saturated NaHCO 3aqueous solution (1 × 30mL) washs thus obtains product, is black oil (0.34g, 1.5mmol, 60%).
F) product that step e obtains is used for the process of similar embodiment 2, adopts 1-(4-fluorophenyl)-5-propylpyrazol-4-amine to replace 1-(4-fluorophenyl)-5-methylpyrazole-4-amine, thus obtain title compound in step 2a. 1h NMR (400MHz, CDCl 3) δ 7.61 (s, 1H), 7.39 (dd, J=8.9, 4.8Hz, 2H), 7.18 (dd, J=8.5, 8.5Hz, 2H), 5.05 (dd, J=9.2, 5.9Hz, 1H), 4.04 (dddd, J=9.2, 8.8, 4.8Hz, 1.2, 1H), 3.89 (ddd, J=9.6, 8.0, 5.2Hz, 1H), 2.90 (dddd, , J=11.6, 8.8, 6.0, 6.0Hz, 1H), 2.76 (dddd, J=13.6, 9.6, 8.4, 5.2Hz, 1H), 2.66 – 2.51 (m, 2H), 2.42 (s, 3H), 1.35 (dddd, J=14.8, 8.8, 6.8, 6.8Hz, 2H), 0.75 (t, J=7.4Hz, 3H), MS:(ES) m/z calculates C 21h 20clF 4n 5o [M+H] +470.1, actual measurement 470.1.
Embodiment 18
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl] oxepane-2-ketone
A) in dichloromethane (38mL) solution of 2-bromo Ketohexamethylene (4g, 22.6mmol), m-CPBA (5.10g, 29.5mmol) is added.After stirring at room temperature 14h, but react 6 hours in refrigerator and cooled.Filters solid also cleans twice with dichloromethane (15mL).Then saturated aqueous sodium thiosulfate (40mL) cancellation filtrate is used.With water and salt water washing organic layer, dry (Na 2sO 4), filter and vacuum concentration.By flash chromatography (SiO 2, 20%EtOAc/ hexane) and purification obtains product, be white solid (3g, 15.5mmol, 69%).
B) to the bromo-2 caprolactone (1g of 3-, the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazoles (0.956g is added in DMF (10mL) solution 5.18mmol), 5.18mmol), add potassium carbonate (1.07g, 7.74mmol) subsequently.Then at 65 DEG C of reacting by heating mixture 8h.After cool to room temperature, between water (20mL) and ethyl acetate (30mL), distribute reactant mixture.With water and salt water washing organic layer, dry (Na 2sO 4), filter and vacuum concentration.By flash chromatography (SiO 2, 25%EtOAc/ hexane) and purification obtains title product, be white solid (0.3g, 1.01mmol, 20%).
Embodiment 19
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl] azacycloheptan-2-one
A) under nitrogen, to 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl] oxepane-2-ketone (0.05g, trimethyl aluminium (126L is added in dichloroethanes (1.0mL) solution 0.168mmol), 2.0M, 0.25mmol), add 1-(4-the fluorophenyl)-5-methylpyrazole-4-amine (0.032g, 0.168mmol) in dichloroethanes (0.7mL) subsequently.Stirred reaction mixture 1 hour, then use the careful cancellation of 1N HCl (2mL) it.Saturated sodium bicarbonate aqueous solution (2mL) is adopted to alkalize water layer also with dichloromethane (2 × 5mL) extraction.With the organic layer that salt water washing merges, dry over sodium sulfate, filter and vacuum concentration.Roughage is directly used in step below.
B) mesyl chloride (0.029g, 0.25mmol) is joined the thick residue of the step a in dichloromethane (1mL) and the solution of triethylamine (0.034g, 0.34mmol) under room temperature.Stirring at room temperature is after 1 hour, to go out reaction with shrend.By ethyl acetate (2 × 5mL) aqueous layer extracted.With the organic layer that salt water washing merges, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in step below.
C) in oxolane (1mL) solution of the thick residue of step b acquisition, add sodium hydride (0.01g, 60%, 0.25mmol) under room temperature, add sodium iodide (0.003g, 0.02mmol) subsequently.Reacting by heating mixture to 60 DEG C also stirs 30 minutes in this temperature.After cool to room temperature, go out reactant mixture also by ethyl acetate (2 × 25mL) aqueous layer extracted with shrend, the organic layer merged with salt water washing, dry (Na 2sO 4), filter and vacuum concentration.The crude product obtained by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtain title compound, is white solid (0.011g, 0.025mmol, 15%, for 3 steps). 1h NMR (400MHz, CDCl 3) δ 7.55 (s, 1H), 7.49 – 7.39 (m, 2H), 7.22 – 7.13 (m, 2H), 4.5 – 4.40 (m, 1H), 4.16 – 4.01 (m, 1H), 3.68 – 3.51 (m, 2H), 2.92 – 2.84 (m, 1H), 2.45-2.38 (m, 1H), 2.35 (s, 3H), 2.26-2.18 (m, 1H), 2.20 (s, 3H), 1.98-1.85 (m, 1H), 0.95-0.77 (m, 1H); MS:(ES) m/z calculates C 21h 20clF 4n 5o [M+H] +470.1, actual measurement 470.1.
Embodiment 20
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl] piperidines-2-ketone
To the bromo-1-of 3-[1-(4-fluorophenyl)-5-methyl-pyrazol-4-yl] piperidines-2-ketone (0.05g, the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazoles (0.031g is added in DMF (1.0mL) solution 0.14mmol), 0.17mmol), add potassium carbonate (0.029g, 0.21mmol) subsequently.After stirring at room temperature 1h, to go out reaction with shrend.Then ethyl acetate (2 × 25mL) aqueous layer extracted is used.With the organic layer that salt water washing merges, dry (Na 2sO 4), filter and vacuum concentration.The crude product obtained by reversed-phase HPLC (C18 post, containing the second nitrile – water of 0.1%TFA, as eluent) purification thus obtain title compound, is white solid (0.015g, 0.025mmol, 23%). 1h NMR (400MHz, CDCl 3) δ 7.65 (s, 1H), 7.44 – 7.35 (m, 2H), 7.22 – 7.13 (m, 2H), 4.94 (dd, J=9.9,6.3Hz, 1H), 3.90 – 3.70 (m, 2H), 2.73 (dddd, J=13.2,11.5,9.8,3.3Hz, 1H), 2.47-2.38 (m, 1H), 2.36 (s, 3H), 2.31 (ddd, J=10.6,5.4,2.4Hz, 1H), 2.17-2.12 (m, 1H), 2.13 (s, 3H); MS:(ES) m/z calculates C 20h 18clF 4n 5o [M+H] +456.1, actual measurement 456.1.
Embodiment 21
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-fluorophenyl)-5-Phenylpyrazole-4-base] pyrrolidin-2-one
A) under nitrogen, to 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl] oxolane-2-ketone (0.063g, trimethyl aluminium (177 μ L are added in dichloroethanes (1.0mL) solution 0.236mmol), 2.0M, 0.354mmol), to add in dichloroethanes (0.7mL)-(4-fluorophenyl)-5-phenyl-pyrazole-4-amine (0.06g, 0.236mmol) subsequently.Stirred reaction mixture adopt after 1 hour the careful cancellation of 1N HCl (2mL) it.Then saturated sodium bicarbonate aqueous solution (2mL) is used to alkalize water layer also with dichloromethane (5mL × 2) extraction.With the organic layer that salt water washing merges, dry over sodium sulfate, filter and vacuum concentration.Roughage is directly used in step below.
B), under room temperature, mesyl chloride (0.041g, 0.36mmol) is joined in the solution of thick residue that the step a in dichloromethane (1mL) obtains and triethylamine (0.049g, 0.49mmol).Stirring at room temperature is after 1 hour, to go out reaction with shrend.By ethyl acetate (2 × 5mL) aqueous layer extracted.With the organic layer that salt water washing merges, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in step below.
C), under room temperature, sodium hydride (0.014g, 60%, 0.35mmol) is heated in oxolane (1mL) solution of the thick residue that step b obtains.Reacting by heating mixture to 60 DEG C also stirs 30 minutes in this temperature.After cool to room temperature, go out reactant mixture also with ethyl acetate (2 × 5mL) aqueous layer extracted and the organic layer with salt water washing merging with shrend, dry (Na 2sO 4), filter and vacuum concentration.The crude product obtained by reversed-phase HPLC (C18 post, containing the second nitrile – water of 0.1%TFA, as eluent) purification thus obtain title compound, is white solid (0.025g, 0.050mmol, 21%, for 3 steps). 1h NMR (400MHz, CDCl 3) δ 7.89 (d, J=0.6Hz, 1H), 7.42 – 7.28 (m, 3H), 7.25 – 7.14 (m, 4H), 7.04 – 6.94 (m, 2H), 4.99 (dd, J=9.2,6.8Hz, 1H), 3.74 – 3.63 (m, 1H), 3.56 – 3.45 (m, 1H), 2.78 (ddt, J=13.2,8.7,6.6Hz, 1H), 2.55 (tq, J=13.4,4.5Hz, 1H), 2.38 (d, J=0.7Hz, 3H); MS:(ES) m/z calculates C 24h 18clF 4n 5o [M+H] +504.1, actual measurement 503.9.
Embodiment 22
The synthesis of 1-[1-(4-chlorphenyl)-5-isopropylpyrazol-4-base]-3-methyl-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
Room temperature is in a nitrogen atmosphere to 1-[1-(4-chlorphenyl)-5-isopropylpyrazol-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one (50mg, DMF (2mL) and NaH (60% is slowly added in solution 0.11mmol), in mineral oil, 16mg, 0.33mmol).Stirring at room temperature, after 10 minutes, adds MeI (34 μ L, 0.55mmol), then stirs 2 hours.Then slow in saturated NH at 0 DEG C 4cl solution (10mL) joins reactant mixture, uses EtOAc (2 × 25mL) to extract subsequently.Dry (MgSO 4) the EtOAc layer that merges, vacuum concentration, by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtain 1-[1-(4-chlorphenyl)-5-isopropyl-pyrazoles-4-base]-3-methyl-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one (17mg, 0.029mmol, 27% productive rate), be tfa salt. 1h NMR (400MHz, methanol-d 4) δ 7.88 (s, 1H), 7.70 (s, 1H), 7.59 (d, J=11.76Hz, 2H), 7.42 (d, J=11.76Hz, 2H), 3.86 – 3.95 (m, 2H), 2.99 – 3.08 (m, 1H), 2.58 – 2.80 (m, 2H), 2.52 (s, 3H), 1.96 (s, 3H), 1.22 (d, J=23.4Hz, 3H), 1.20 (d, J=23.4Hz, 3H); MS:(ES) m/z calculates C 22h 23clF 3n 5o [M+H]+466.9, actual measurement 466.1.
Embodiment 23
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[1-(3-fluorophenyl)-5-(furan-3-base)-1H-pyrazoles-4-base] pyrrolidin-2-one
A) (ethoxy ethylene base) cyan-acetic ester (2.37g, 14.0mmol) and 3-fluorophenyl hydrazine hydrochloride (2.28g, 14.0mmol) are suspended in ethanol (50mL).In 80 DEG C of reacting by heating mixture 3 days, then EtOH was removed in decompression.Crude product mixture is suspended in dichloromethane, removes insoluble material by filtering.Concentrating under reduced pressure filtrate is also passed through silica gel column chromatography (5 – 20% ethyl acetate, in hexane) purification thus obtains 5-amino-1-(3-fluorophenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (930mg, 3.73mmol, 27% productive rate).
B) acetonitrile (5mL) is suspended at ambient temperature 5-amino-1-(3-fluorophenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (518mg, 2.08mmol).Add diiodomethane (675 μ L, 8.38mmol), then add amyl nitrite (565 μ L, 4.21mmol).Within 1 hour, then distribute between water and ethyl acetate 50 DEG C of reacting by heating.Be extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate, after solvent is removed in decompression, adopt silica gel column chromatography (10 – 25% ethyl acetate, in hexane) purification of crude material thus obtain the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (589mg, 1.64mmol, 79% productive rate).
C) the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-carboxylic acid, ethyl ester (589mg, 1.64mmol) be dissolved in the mixture of oxolane (5mL), 1.5N LiOH (1.6mL) and methanol (1.5mL), stir the mixture and spend the night.Most of oxolane is removed through reactant mixture by nitrogen purge gas flow gently.Add water and 1N HCl (2.4mL), abundant ultrasonic mixture thus be settled out carboxylic acid.Filter carboxylic acid and clean with water.After vacuum drying, obtain 5-iodo-1-(3-fluorophenyl)-1H-pyrazoles-4-carboxylic acid (488mg, 1.47mmol, 90% productive rate).This material does not need to be further purified for next step.
D) first under 4A molecular sieve exists, the dry tert-butyl alcohol (3.5mL) of stirred overnight is passed through at 50 DEG C.In this solvent, the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-carboxylic acid (488mg is added in ambient temperature, 1.47mmol), add triethylamine (204 μ L, 1.46mmol) and diphenylphosphoryl azide (334 μ L, 1.54mmol) subsequently.Reacting by heating mixture to 60 DEG C also stirs and spends the night.Then react with diluted ethyl acetate.Silica gel is joined reactant mixture and decompression remove solvent thus on silica gel pre-absorption roughage.Then silica gel column chromatography (6 – 20% ethyl acetate are adopted, in hexane) purified material thus obtain the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-base-carbamic acid 1,1-dimethyl ethyl ester (482mg, 1.20mmol, 81% productive rate).
E) to comprising the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-base-carbamic acid 1,1-dimethyl ethyl ester (150mg, the 2-(2 in toluene (2.5mL) is added in bottle 0.372mmol), 5-dihydro-3-furyl)-4,4,5,5-tetramethyl-1,3-2-dioxaborolanes (100mg, 0.512mmol).Add dioxane (0.56mL), add wet chemical (2M, 560 μ L, 1.12mmol) subsequently.Inflated with nitrogen crosses bottle, adds tetrakis triphenylphosphine palladium (20.1mg, 0.0174mmol) subsequently.Spend the night at 100 DEG C of stirring reactions.After cool to room temperature, with ethyl acetate and water diluting reaction.Stratum disjunctum is also extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, adopt silica gel column chromatography (5 – 33% ethyl acetate, in hexane) purification of crude material thus obtain Suzuki product (55.4mg, 0.160mmol, 43% productive rate).At ambient temperature this material of the HCl treatment in dioxane (4N, 1mL) 2 hours.After excessive hydrochloric acid and dioxane are removed in decompression, roughage is dissolved in ethyl acetate and washs with saturated sodium bicarbonate solution.Be extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.Decompression is removed solvent thus is obtained crude product, and its main component is 5-(3-furyl)-1-(3-fluorophenyl)-4-amino-1H-pyrazoles (48.4mg).
F) roughage (48.4mg) obtained from preceding step and 3-(3-trifluoromethyl-4-chloro-5-methyl isophthalic acid H-pyrazol-1-yl) dihydro-2 (3H)-furanone (47mg, 0.18mmol) are dissolved in dichloroethanes (0.5mL).In this mixture, trimethyl aluminium (2M, in toluene, 0.12mL, 0.24mmol) is added under room temperature.Stirring at room temperature reacts two hours.Add hydrochloric acid (1N) and dichloromethane and stratum disjunctum.Use dichloromethane extraction water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.Decompression is removed solvent thus is obtained crude product (62.0mg), and it is dissolved in dichloromethane (1mL).Add triethylamine (84 μ L, 0.60mmol) in ambient temperature, drip mesyl chloride (19 μ L, 0.24mmol) subsequently.Identical temperature stirring reaction 30 minutes.Add saturated sodium bicarbonate solution and use dichloromethane extraction product three times.The dry organic layer merged on anhydrous sodium sulfate.Decompression is dissolved in oxolane (1mL) at ambient temperature crude product after removing solvent.Sodium hydride (60%, be dispersed in oil) is added until do not observe more bubbling with little deal.Spend the night at this temperature stirring reaction.Water and ethyl acetate are joined reactant mixture and stratum disjunctum.Be extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.This solution is by silicagel pad and fully wash by ethyl acetate thus remove baseline impurity.Then this material of concentrating under reduced pressure is also by reversed-phase HPLC (C18 post, 20 – 95% acetonitrile/water, containing 0.1% trifluoroacetic acid) be further purified thus obtain 3-[the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[1-(3-fluorophenyl)-5-(furan-3-base)-1H-pyrazoles-4-base] pyrrolidin-2-one (2.7mg, 0.0055mmol, 3% productive rate, through 4 steps). 1h NMR (400MHz, CDCl 3) δ 7.80 (s, 1H), 7.31 – 7.47 (m, 3H), 7.33 (dd, J=8.0,6.4Hz, 1H), 7.14 (d, J=7.2Hz, 1H), 7.04 – 7.10 (m, 1H), 6.45 (s, 1H), 5.03 (dd, J=9.6,6.8Hz, 1H), 3.88 (ddd, J=9.4,9.4,5.1Hz, 1H), 3.67 (ddd, J=10.0,8.4,6.4Hz, 1H), 2.78 – 2.87 (m, 1H), 2.66 (dddd, J=17.2,8.2,4.3,4.3Hz, 1H), 2.40 (s, 3H); MS:(ES) m/z calculates C 22h 16n 5o 2clF 4[M+H] +494.1, actual measurement 494.0.
Embodiment 24
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[5-cyclopropyl-1-(3-fluorophenyl)-1H-pyrazoles-4-base] pyrrolidin-2-one
A) in reaction bottle, the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-base is loaded)-carbamic acid 1,1-dimethyl ethyl ester (150mg, 0.372mmol), cyclopropylboronic acid (43.0mg, 0.504mmol), tricyclohexyl phosphine (10.0mg, 0.0357mmol) with potassium phosphate (276mg, 1.30mmol).Add toluene (1.7mL) and water (85 μ L).Purge reaction with nitrogen, add acid chloride (4.2mg, 0.019mmol) subsequently.In 100 DEG C of reacting by heating mixture two hours.Add more tricyclohexyl phosphines (10.3mg, 0.0367mmol) and acid chloride (4.5mg, 0.020mmol), stir more than 5 hours at 100 DEG C.Add BrettPhos (2-(dicyclohexyl) 3,6-dimethoxy-2 ', 4 ', 6 '-triisopropyl-1,1 '-diphenylphosphine, 10.7mg, 0.0199mmol) and acid chloride (3.9mg, 0.0174mmol) spending the night at 100 DEG C of further stirred reaction mixtures.After cool to room temperature, add water and ethyl acetate and stratum disjunctum.Be extracted with ethyl acetate water layer twice again, on anhydrous sodium sulfate the dry organic layer merged.After solvent is removed in decompression, adopt silica gel column chromatography (7 – 80% ethyl acetate, in hexane) purification of crude material thus obtain Suzuki product (41.4mg, 0.130mmol, 35% productive rate).Hydrochloric acid in dioxane (4N, 1mL) is added and ambient temperature stirring reaction 4 hours in this product.Decompression distributes reactant mixture after removing solvent between ethyl acetate and saturated sodium bicarbonate solution.Stratum disjunctum is also extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.Decompression is removed solvent and is obtained 5-(3-cyclopropyl)-1-(3-fluorophenyl)-4-amino-1H-pyrazoles (25.6mg, 0.118mmol, 91% productive rate), and it does not need to be further purified for next step.
B) product (25.6mg of preceding step acquisition, 0.118mmol) be dissolved in dichloroethanes (0.5mL) with 3-(3-trifluoromethyl-4-chloro-5-methyl isophthalic acid H-pyrazol-1-yl) dihydro-2 (3H)-furanone (49.0mg, 0.182mmol).Room temperature adds trimethyl aluminium (2M, in toluene, 0.12mL, 0.24mmol) in this mixture.Stirring at room temperature reacts 2 hours.Add more trimethyl aluminiums (2M, in toluene, 0.7mL, 1.4mmol), at room temperature stirring reaction two hours further.Then hydrochloric acid (1N) and dichloromethane is added and stratum disjunctum.Use dichloromethane extraction water layer twice again.The organic layer merged with saturated sodium bicarbonate solution washing is once and on anhydrous sodium sulfate dry.Decompression is removed solvent thus is obtained crude product (73.2mg), and it is dissolved in dichloromethane (1mL).Mesyl chloride (23 μ L, 0.30mmol) and triethylamine (105 μ L, 0.753mmol) is added in ambient temperature.Identical temperature stirring reaction 2 hours.Add saturated sodium bicarbonate solution and use dichloromethane extraction product three times.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, crude product is dissolved in oxolane (1mL) in ambient temperature.Sodium hydride (dispersion in 60% oil) is added until do not observe more bubbling with little deal.This temperature stirring reaction 1 hour.Saturated ammonium chloride solution and ethyl acetate join reactant mixture and stratum disjunctum.And then be extracted with ethyl acetate water layer twice.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, 2-methyl-4-Trifluoromethyl-1 H-imidazoles (the 16.7mg in dimethyl formamide (0.5mL) is adopted at 55 DEG C, 0.111mmol) process crude product 3 hours with potassium carbonate (90.2mg, 0.653mmol).Then ethyl acetate and water are joined reactant mixture.Stratum disjunctum is also extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, adopt silica gel column chromatography (50 – 60% ethyl acetate, in hexane) purification of crude material thus obtain 3-[the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[1-(3-fluorophenyl)-5-(ring third-3-base)-1H-pyrazoles-4-base] pyrrolidin-2-one, it is by adopting reversed-phase HPLC (C18 post, 20 – 95% acetonitrile/water, containing 0.1% trifluoroacetic acid) be further purified (15.0mg, 0.0346mmol, 29% productive rate, through three steps). 1h NMR (400MHz, CDCl 3) δ 7.61 (s, 1H), 7.37 – 7.44 (m, 2H), 7.33 (ddd, J=9.6, 2.0, 2.0Hz, 1H), 7.04 – 7.09 (m, 1H), 5.04 (dd, J=9.6, 6.8Hz, 1H), 4.10 (ddd, J=9.6, 9.6, 4.8Hz, 1H), 3.89 (ddd, J=9.0, 8.0, 5.6Hz, 1H), 2.97 (dddd, J=14.8, 8.4, 8.4, 5.6Hz, 1H), 2.73 (dddd, J=17.2, 8.4, 5.2, 5.2Hz, 1H), 2.42 (s, 3H), 1.79 (tt, J=10.4, 5.6Hz, 1H), 0.71 – 0.82 (m, 2H), 0.36 – 0.40 (m, 2H), MS:(ES) m/z calculates C 21h 18n 5oClF 4[M+H] +468.2, actual measurement 468.1.
Embodiment 25
The synthesis of 3-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[the iodo-1H-pyrazoles of 1-(3-fluorophenyl)-5--4-base] pyrrolidin-2-one
A) in ambient temperature, the hydrochloric acid in dioxane (4N, 3mL) is joined the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles-4-base-carbamic acid 1,1-dimethyl ethyl ester (348mg, 0.864mmol).Spend the night at identical temperature stirring reaction.Solvent is removed in decompression.Roughage is dissolved in ethyl acetate and saturated sodium bicarbonate solution.Stratum disjunctum is also extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, adopt silica gel column chromatography (20 – 60% ethyl acetate, in hexane) purification of crude material thus obtain the iodo-1-of 5-(3-fluorophenyl)-1H-pyrazoles (210mg, 0.695mmol, 80% productive rate).
B) unhindered amina (211mg of preceding step acquisition, 0.695mmol) be dissolved in dichloroethanes (2.3mL) with 3-(3-trifluoromethyl-4-chloro-5-methyl isophthalic acid H-pyrazol-1-yl) dihydro-2 (3H)-furanone (229mg, 0.853mmol).In this mixture, trimethyl aluminium (2M, in toluene, 0.7mL, 1.4mmol) is added under room temperature.Stirring at room temperature reacts two hours.Add more trimethyl aluminiums (2M, in toluene, 0.3mL, 0.6mmol) and the further stirring reaction of room temperature two hours.Add hydrochloric acid (1N) and dichloromethane, mixture passes through Celite pad.Stratum disjunctum, then use dichloromethane extraction water layer twice.The dry organic layer merged on anhydrous sodium sulfate.Decompression is removed solvent thus is obtained crude product, and it is dissolved in dichloromethane (2mL).Mesyl chloride (81 μ L, 1.04mmol) and triethylamine (483 μ L, 3.47mmol) is added in ambient temperature.Identical temperature stirring reaction 30 minutes.Add saturated sodium bicarbonate solution and use dichloromethane extraction product three times.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, crude product is dissolved in oxolane (7.5mL) in ambient temperature.Sodium hydride (dispersion in 60% oil) is added until do not observe more bubbling with little deal.This temperature stirring reaction 1 hour.Saturated ammonium chloride solution and ethyl acetate are joined reactant mixture and stratum disjunctum.Be extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, adopt silica gel column chromatography (20 – 40% ethyl acetate, in hexane) purification of crude material thus obtain 3-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[the iodo-1H-pyrazoles of 1-(3-fluorophenyl)-5--4-base] pyrrolidin-2-one (126mg, 0.227mmol, 33% productive rate, through 3 steps).Adopt this material of methanol trituration to be further purified (output 42.5mg). 1h NMR (400MHz, CDCl 3) δ 7.80 (s, 1H), 7.45 (ddd, J=8.2,8.2,5.9Hz, 1H), 7.34 (dd, J=8.2,2.0Hz, 1H), 7.28 (ddd, J=9.4,2.0,2.0Hz, 1H), 7.16 (ddd, J=8.2,8.2,2.4Hz, 1H), 5.06 (dd, J=9.6,6.8Hz, 1H), 4.08 (ddd, J=9.6,9.6,4.8Hz, 1H), 3.94 (ddd, J=9.6,8.0,6.4Hz, 1H), 3.00 (dddd, J=15.6,8.4,8.4,6.4Hz, 1H), 2.73 (dddd, J=17.2,8.0,4.8,4.8Hz, 1H), 2.42 (s, 3H); MS:(ES) m/z calculates C 18h 13n 5oClF 4i [M+H] +554.0, actual measurement 554.0.
Embodiment 26
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[5-propyl group-1-(3-fluorophenyl)-1H-pyrazoles-4-base] pyrrolidin-2-one
A) by potassium carbonate (43.1mg, 0.312mmol) join and comprise 3-[4-chloro-5-methyl-3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[the iodo-1H-pyrazoles of 1-(3-fluorophenyl)-5--4-base] pyrrolidin-2-one (83.0mg, in flask 0.150mmol), add toluene (0.5mL) and dioxane (0.1mL) subsequently.4 are added in this mixture, 4,5,5-tetramethyl-2-(1-methyl ethylene)-1,3-2-dioxaborolanes (56 μ L, 0.30mmol), add water (25 μ L), 2-dicyclohexylphosphontetrafluoroborate-2 subsequently ', 6 '-dimethoxydiphenyl (SPhos, 6.2mg, 0.015mmol) with acid chloride (3.3mg, 0.015mmol).Nitrogen is adopted to purge reactant mixture and spend the night 100 DEG C of stirrings.After cooling, add water and ethyl acetate.Stratum disjunctum is also extracted with ethyl acetate water layer twice again.The dry organic layer merged on anhydrous sodium sulfate.After solvent is removed in decompression, adopt silica gel column chromatography (30 – 100% ethyl acetate, in hexane) purification of crude material thus obtain Suzuki product (24.4mg, 0.0522mmol, 35% productive rate).Reclaim some iodine compound raw materials and some de-iodine by-products.Suzuki product is dissolved in the mixture of ethyl acetate (5mL) and methanol (5mL).Add palladium/carbon (10%, wet, 9.7mg).Adopt Pa Er instrument hydrogenated mixture 1 hour under 35psi hydrogen, then hydrogenation 1 hour under 45psi hydrogen.After adopting nitrogen purge reactant mixture, add more palladium/carbon (10%, wet, 10.3mg) and solvent (ethyl acetate: methanol=1:1,8mL), under 45psi hydrogen, reactant mixture is hydrogenated 1 hour further.Filter reactant mixture by Celite pad and adopt ethyl acetate: methanol (1:1,10mL) mixture thoroughly cleans.After solvent is removed in decompression, adopt reversed-phase HPLC (C18 post, 20 – 95% acetonitrile-waters, containing 0.1% trifluoroacetic acid) purification of crude material thus obtain 3-[the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl]-1-[5-propyl group-1-(3-fluorophenyl)-1H-pyrazoles-4-base] pyrrolidin-2-one (14.4mg, 0.0306mmol, 59% productive rate). 1h NMR (400MHz, CDCl 3) δ 7.60 (s, 1H), 7.43 (ddd, J=8.0,8.0,6.0Hz, 1H), 7.14 – 7.22 (m, 3H), 5.02 (dd, J=9.2,5.6Hz, 1H), 4.02 (ddd, J=9.2,5.2,5.2Hz, 1H), 3.86 (ddd, J=9.6,8.0,5.6Hz, 1H), 2.88 (dddd, J=14.4,8.8,8.8,6.0Hz, 1H), 2.73 (dddd, J=17.2,8.4,5.6,5.6Hz, 1H), 2.57 – 2.68 (m, 2H), 2.41 (s, 3H), 1.35 (qt, J=9.6,9.6Hz, 2H), 0.74 (t, J=7.6Hz, 3H); MS:(ES) m/z calculates C 21h 20n 5oClF 4[M+H] +470.1, actual measurement 470.1.
Embodiment 27
The synthesis of 3-(the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazol-1-yl)-1-(1-(4-fluorophenyl)-5-isopropyl-1H-pyrazoles-4-base)-5-methylpyrrolidin-2-ketone
A) under room temperature under nitrogen by trimethyl aluminium (1.0mL, 2mmol, 2M solution, in toluene) add 1-(4-fluorophenyl)-5-isopropyl-1H-pyrazoles-4-amine (219mg, 1mmol) in anhydrous dichloroethanes (5mL) and cis/trans-α-bromo-gamma-valerolactone in batches.Stir after 2 hours, go out with shrend and react and use 10mL EtOAc and 0.5mL 6N HCl dilution mixture thing.With water and salt water washing organic layer, dry over magnesium sulfate, filter and vacuum concentration.Residue is dissolved in CH 2cl 2(6mL), Et is added 3n (0.25mL, 1.8mmol) and mesyl chloride (0.13mL, 1.65mmol).Stir after 1 hour, use 1M NaHSO 4washing reaction mixture dry organic layer over magnesium sulfate, filter and vacuum concentration thus obtain yellow oil.Residue is dissolved in THF (10mL) and adds NaI (30-40mg).Then sodium hydride (90mg, 2.3mmol) is joined reacting slurry.Stir after 16 hours, use saturated NH 4cl cancellation reaction and concentrating under reduced pressure thus remove THF.With water (10mL) dilution mixture thing also with EtOAc (3 × 5mL) extraction.Dry organic layer over magnesium sulfate, filters, concentrates and pass through flash chromatography (SiO 2, 5-90%EtOAc/ hexane) and purification thus obtain product (219mg, 0.38mmol, 38%) is water white oil.
B) in the product (57mg, 0.15mmol) of step a acquisition in DMF (1mL) and the solution of the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazoles (138mg, 0.75mmol), K is added 2cO 3(104mg, 0.75mmol).Serosity is heated to 60 DEG C of 1h and then adopts EtOAc (4mL). dilution.With water and saline purging compound and vacuum concentration.Obtaining the cis/trans formula mixture (40mg, 0.083mmol) of title compound by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification of crude residue, is white solid.Cis/trans formula mixture 1h NMR (400MHz, CDCl 3) δ 7.46 (s, 054H), 7.43 (s, 0.46H), 7.42-7.36 (m, 2H), 7.20-7.15 (m, 2H), 5.11 (m, 1H), 4.35-4.27 (m, 0.46H), 4.10-4.01 (m, 0.54H), 3.06 – 2.84 (m, 2H), 2.68-2.60 (m, 0.46H), 2.43 (s, 1.38H), 2.40 (s, 1.62H), 2.34-2.25 (m, 0.54H), 1.40 (d, J=6.3Hz, 1.62H), 1.37 (d, J=6.6Hz, 1.38H), 1.17 (d, J=7.1Hz, 1.38H), 1.16 (d, J=7.0Hz, 1.62H), 1.12 (d, J=7.1Hz, 1.62H), 1.04 (d, J=7.4Hz, 1.38H), MS:(ES) m/z calculates C 22h 23clF 4n 6o [M+H] +484.1, actual measurement 483.9.
Embodiment 28
The synthesis of 1-(1-(4-fluorophenyl)-5-isopropyl-1H-pyrazoles-4-base)-5-methyl-3-(2-methyl-4-(trifluoromethyl)-1H-imidazoles-1-base) pyrrolidin-2-one hydrochlorate
The process adopting embodiment 27 to describe prepares title compound, replaces the chloro-5-methyl of 4--3-(trifluoromethyl)-1H-pyrazoles in step b 2-methyl-4-(trifluoromethyl)-1H-imidazoles.Cis/trans formula mixture 1h NMR (400MHz, CD 3oD) δ 8.50 (s, 064H), 8.43 (s, 0.36H), 7.64 (s, 1H), 7.52-7.49 (m, 2H), 7.32 (t, J=8.2Hz, 2H), 5.82-5.76 (m, 1H), 4.26-4.20 (m, 1H), 3.16-2.96 (m, 2H), 2.82-2.79 (m, 3H), 1.48 (m, 1H), 2.29 (m, 1H), 1.37 (m, 2H), 1.19-1.15 (m, 6H); MS:(ES) m/z calculates C 22h 23f 4n 5o [M+H] +450.2, actual measurement 450.0.
Embodiment 29
The synthesis of 1-[1-(4-fluorophenyl)-5-isopropoxy pyrazoles-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) by the iodo-fluorobenzene of the 4-(2.42g in DMSO (20mL), 11mmol), 4-nitro-1H-pyrazoles (1.00g, 10mmol), oxine (0.15g, 1mmol), CuI (0.192g, 1mmol) and the mixture of potassium carbonate (2.78g, 20mmol) 135 DEG C of heated overnight.After cool to room temperature, adopt 30mL water diluted reaction mixture and be extracted with ethyl acetate.Organic layer is washed subsequently, dry (Na with saturated sodium bicarbonate aqueous solution 2sO 4), filter and vacuum concentration.By flash chromatography (SiO 2, 10%-20%EtOAc, in hexane) and purification obtains product needed for 1.02g (4.9mmol, 49%).
B) at-78 DEG C, in the solution of 1-(4-the fluorophenyl)-4-nitro-pyrazole (1.02g, 4.9mmol) in 10mL THF, LiHMDS (in 1M, THF, 5.8mL, 5.8mmol) is added under a nitrogen.After 30 minutes, drip 1,1,1,2,2,2-perfluoroethane (1.31g, 5.5mmol) in 6mL THF.Stirred reaction mixture 1 hour again, uses the cancellation of 20mL saturated aqueous ammonium chloride subsequently.After room temperature of rising again, extract mixture with EtOAc.Dry (Na 2sO 4) organic layer, filter and vacuum concentration.By flash chromatography (SiO 2, 5%-15%EtOAc, in hexane) and the roughage that obtains of purification thus obtain 0.61g product (2.5mmol, 52%).
C) at 0 DEG C, in the solution of the isopropyl alcohol (0.12g, 2mmol) in 1mL NMP, NaH (0.085g, 2mmol) is added under a nitrogen.After room temperature of rising again, add the chloro-1-of 5-(4-fluorophenyl)-4-nitro-pyrazole (0.24g, 1mmol).The mixture obtained 100 DEG C of heating 3 hours.After cool to room temperature, react with saturated sodium bicarbonate aqueous solution cancellation and extract with EtOAc.Dry (Na subsequently 2sO 4) organic layer, filter and vacuum concentration.Roughage is directly used in next step.
The mixture of the thick residue d) obtained by the step c in 2mL EtOH, iron powder (0.23g, 4mmol) and 100 μ L 6N HCl aqueous solutions was 80 DEG C of heating 20 minutes.After cool to room temperature, with 20mL saturated sodium bicarbonate aqueous solution and 40mL EtOAc diluted reaction mixture.The suspension that stirring obtains 10 minutes, then passes through diatomite filtration.Be separated organic layer, use salt water washing, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
E) the thick residue (0.042g obtained to the steps d in 1mL dichloroethanes at 0 DEG C, 0.17mmol) He 2, Me is added in the mixture of 5-bis-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] Ketocyclopentane (0.053g, 0.22mmol) 3al (2N, in toluene, 180 μ L, 0.36mmol).Stirring at room temperature, after 2 hours, also extracts with extraction EtOAc with 30mL water diluted reaction mixture.Organic layer is washed subsequently, dry (Na with saturated sodium bicarbonate aqueous solution 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
F) to 1mL CH 2cl 2in the thick residue that obtains of step e and Et 3msCl (28 μ L, 0.36mmol) is added in the solution of N (0.1mL).Stirring at room temperature is after 2 hours, with 20mL saturated sodium bicarbonate aqueous solution and 40mL EtOAc diluted reaction mixture.Be separated organic layer subsequently, use salt water washing, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
G) at 0 DEG C, in the solution of the thick residue of the step f acquisition in 1mL THF, NaH (0.019g, 0.46mmol) is added.Room temperature was after 5 minutes, 60 DEG C of heating blends 2 hours.After cool to room temperature, with 20mL saturated sodium bicarbonate aqueous solution and 40mL EtOAc diluted reaction mixture.Be separated organic layer subsequently, use salt water washing, dry (Na 2sO 4), filter and vacuum concentration.By flash chromatography (SiO 2, 60%-100%EtOAc, in hexane) and purification obtains title compound, be white solid (0.026g, 0.056mmol, 8.4%, 7 steps). 1h NMR (400MHz, CDCl 3) δ 7.81 (s, 1H), 7.70 – 7.61 (m, 2H), 7.20 – 7.14 (m, 2H), 4.96 (t, J=9.3Hz, 1H), 4.15 (p, J=8.0Hz, 1H), 3.98 (t, J=7.8Hz, 1H), 3.89 (q, J=7.8Hz, 1H), 2.93 – 2.80 (m, 1H), 2.51 (s, 3H), 2.41 – 2.26 (m, 1H), 1.20 (m, 6H) .MS:(ES) m/z calculates C 19h 20f 4n 6o 1[M+H] +452.1, actual measurement 452.3.
Embodiment 30
The synthesis of 1-[1-(4-fluorophenyl)-5-dimethylamino pyrazoles-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) by the mixture of chloro-for the 5-in 1mL DMF 1-(4-fluorophenyl)-4-nitro-pyrazole (0.20g, 0.8mmol) and dimethyl amine (2M, in water, 0.80mL, 1.6mmol) 80 DEG C of heating 2 hours.After cool to room temperature, extract with EtOAc with 20mL water diluted reaction mixture.Use salt water washing organic layer subsequently, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
The mixture of the crude product b) obtained by the step a in 1mL EtOH, iron powder (0.14g, 2.5mmol) and 100 μ L 6N HCl aqueous solutions was 80 DEG C of heating 20 minutes.After cool to room temperature, with 20mL saturated sodium bicarbonate aqueous solution and 40mL EtOAc diluted reaction mixture.Stir the suspension obtained and then pass through diatomite filtration in 10 minutes.Be separated organic layer, use salt water washing, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
C) at 0 DEG C, to the thick residue (0.053g that the step b in 1mL dichloroethanes obtains, 0.23mmol) and in the solution of 2,5-bis-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] Ketocyclopentane (0.064g, 0.27mmol) add Me 3al (2N, in toluene, 130 μ L, 0.27mmol).Stirring at room temperature is after 2 hours, extracts with EtOAc with 30mL saturated sodium bicarbonate aqueous solution diluted reaction mixture.Use salt water washing organic layer subsequently, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
D) to 1mL CH 2cl 2in the thick residue that obtains of step c and Et 3msCl (36 μ L, 0.46mmol) is added in the solution of N.Stirring at room temperature is after 2 hours, with 20mL saturated sodium bicarbonate aqueous solution and 40mL EtOAc diluted reaction mixture.Be separated organic layer subsequently, use salt water washing, dry (Na 2sO 4), filter and vacuum concentration.Roughage is directly used in next step.
E) at 0 DEG C, in the solution of the thick residue obtained to the steps d in 1mL THF, NaH (0.019g, 0.46mmol) is added.Room temperature was after 5 minutes, 60 DEG C of heating blends 2 hours.After cool to room temperature, with 20mL saturated sodium bicarbonate aqueous solution and 40mL EtOAc diluted reaction mixture.Be separated organic layer subsequently, use salt water washing, dry (Na 2sO 4), filter and vacuum concentration.By flash chromatography (SiO 2, 60%-100%EtOAc, in hexane) and purification obtains title compound, be white solid (0.015g, 0.034mmol, 15%, 3 steps). 1h NMR (400MHz, CDCl 3) δ 7.62 – 7.58 (m, 2H), 7.53 (s, 1H), 7.23 (s, 1H), 7.18 – 7.11 (m, 2H), 4.98 (t, J=7.5Hz, 1H), 4.12 (q, J=7.2Hz, 1H), 3.94 – 3.78 (m, 1H), 2.90 – 2.83 (m, 1H), 2.66 (s, 6H), 2.51 (s, 1H), 2.39 – 2.33 (m, 1H) .MS:(ES) m/z calculates C 19h 20f 4n 6o 1[M+H] +437.2, actual measurement 437.2.
Embodiment 31
The synthesis of 1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) at 55 DEG C of heating 1-(4-fluorophenyl)-5-isopropyl-pyrazoles-4-amine (0.070g, 0.32mmol), 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone (0.070g, 0.30mmol) and AlMe 3the mixture of (0.50mL, 1.0mmol, 2M/ toluene) 1.5 hours.Then mixture is cooled to room temperature, dilutes with ammonium hydroxide aqueous solution and extract with EtOAc.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration, and by flash chromatography (SiO 2, 0 ~ 20%MeOH/CH 2cl 2gradient elution) purification thus obtain 3-[[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] amino]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] the third-1-alcohol (0.030g, 24%).
B) stirring at room temperature CH 2cl 2(2mL) 3-[[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] is amino]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] the third-1-alcohol (0.030g in, 0.070mmol), mesyl chloride (0.040mL, 0.51mmol) and NEt 3the mixture of (0.10mL, 0.71mmol) 10 minutes.Then vacuum concentration thus obtain required methanesulfonates.
C) the above-mentioned methanesulfonates of stirring at room temperature (~ 0.070mmol) and NaH (0.050g, 1.25mmol, in 60% mineral oil) are at the mixture 10 minutes of THF (4mL).Then H is used 2o (20mL) cancellation also extracts with EtOAc (50mL).Dry organic layer on anhydrous sodium sulfate, vacuum concentration also passes through reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtains title compound (0.022g, 57%, tfa salt), is white solid. 1h NMR (tfa salt) (400MHz, CDCl 3) δ 7.58 (s, 1H), 7.39 (dd, J=8.4,4.8Hz, 2H), 7.28 (s, 1H), 7.20 (dd, J=8.4,8.4Hz, 2H), 5.05 (dd, J=10.6,9.0Hz, 1H), 3.90 (m, 1H), 3.82 (dd, J=9.0,9.0Hz, 1H), 3.01 (septet, J=7.0Hz, 1H), 2.90 (m, 1H), 2.60 (s, 3H), 2.41 (m, 1H), 1.222 (d, J=7.2Hz, 3H), 1.218 (d, J=7.2Hz, 3H); MS:(ES) m/z calculates C 21h 21f 4n 5o (free form) [M+H] +436.2, actual measurement 436.2.
Embodiment 32
The synthesis of 1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-3-[5-methyl-3-(trifluoromethyl) pyrazol-1-yl] pyrrolidin-2-one
A) 1-(4-fluorophenyl)-5-isopropylpyrazol-4-amine (1.0g, 4.54mmol), 3-bromine oxolane-2-ketone (0.462mL, 5.0mmol) and AlMe in DCE (50mL) is at room temperature stirred 3the mixture of (3.4mL, 6.8mmol, 2M, in toluene) 2 hours, stirs 45 minutes at 50 DEG C subsequently.Then by mixture cool to room temperature, adopt 1N HCl (50mL) cancellation and extract with EtOAc (100mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 100%EtOAc/CH 2cl 2gradient elution) purification thus obtain the bromo-N-of 2-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-4-hydroxy-butyramide (1.38g, 79%).
B) CH is stirred at 0 DEG C 2cl 2(50mL) the bromo-N-of the 2-in [1-(4-fluorophenyl)-5-isopropyl-pyrazoles-4-base]-4-hydroxy-butyramide (1.38g, 3.59mmol), mesyl chloride (0.36mL, 4.65mmol) and NEt 3the mixture of (0.75mL, 5.35mmol) 40 minutes.Then use water (50mL) quench mix, and extract with EtOAc (100mL).Be separated organic layer, dry on anhydrous sodium sulfate and vacuum concentration thus obtain required methanesulfonates (1.65g, 99%).
C) in 50 DEG C of mixture stirring in THF (7mL) above-mentioned methanesulfonates (0.350g, 0.75mmol) and NaH (0.200g, 5.0mmol, in 60% mineral oil) 30 minutes.Then be cooled to room temperature, adopt saturated NH 4cl aqueous solution (50mL) cancellation also extracts with EtOAc (50mL).Dry organic layer on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 80%EtOAc/CH 2cl 2gradient elution) purification thus obtain the bromo-1-of 3-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.160g, 58%)
D) the bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.023g in DMF (1mL) is stirred at 60 DEG C, 0.063mmol), 5-methyl-3-(trifluoromethyl)-1H-pyrazoles (0.040g, 0.27mmol) and K 2cO 3the mixture of (0.060g, 0.43mmol) 1 hour.Then cool to room temperature, with water (30mL) cancellation also with EtOAc (100mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 100%EtOAc/ hexanes gradient elution) and purification thus obtain title compound (0.022g, 80%). 1h NMR (400MHz, CDCl 3) δ 7.52 (s, 1H), 7.37 (dd, J=9.2,4.8Hz, 2H), 7.17 (dd, J=8.6,8.6Hz, 2H), 6.32 (s, 1H), 5.05 (dd, J=9.2,5.6Hz, 1H), 4.07 (m, 1H), 3.80 (m, 1H), 2.84 – 3.02 (m, 2H), 2.74 (m, 1H), 2.45 (s, 3H), 1.21 (d, J=7.6Hz, 3H), 1.11 (d, J=6.8Hz, 3H); MS:(ES) m/z calculates C 21h 21f 4n 5o [M+H] +436.1, actual measurement 436.1.
Embodiment 33
The synthesis of 1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-3-[3-(1H-imidazoles-2-base) pyrazolo [3,4-b] pyridine-1-base] pyrrolidin-2-one
A) the bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.080g in DMF (2.5mL) is stirred at 60 DEG C, 0.22mmol), 1H-pyrazolo [3,4-b] pyridine-3-formonitrile HCN (0.045g, 0.31mmol) and K 2cO 3the mixture of (0.070g, 0.50mmol) 1 hour.Then cool to room temperature, with water (30mL) cancellation also with EtOAc (100mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 20 ~ 100%EtOAc/ hexanes gradient elution) thus obtain 1-[1-[1-(4-fluorophenyl)-5-isopropyl-pyrazoles-4-base]-2-oxo-pyrroli-3-base] pyrazolo [3,4-b] pyridine-3-formonitrile HCN (0.085g, 88%).
B) ethane-1 is stirred at 100 DEG C, 1-[1-[1-(4-fluorophenyl)-5-isopropyl-pyrazoles-4-base]-2-oxo-pyrroli-3-base] pyrazolo [3 in 2-diamidogen (1mL), HOAc (0.1mL) and EtOH, 4-b] mixture 1 hour of pyridine-3-formonitrile HCN (0.082g, 0.19mmol) (2.5mL).Then by mixture cool to room temperature, saturated NaHCO is used 3aqueous solution (50mL) cancellation also extracts with EtOAc (100mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration thus obtain 3-[3-(4,5-dihydro-1H-imidazoles-2-base) pyrazolo [3,4-b] pyridine-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.085g, 94%).
C) 3-[3-(4 in DMSO (2.5mL) is stirred at 80 DEG C, 5-dihydro-1H-imidazoles-2-base) pyrazolo [3,4-b] pyridine-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.085g, 0.18mmol) and wear the mixture 1 hour of this Martin's oxidant (0.153g, 0.36mmol).Then cool to room temperature, uses saturated NaHCO 3aqueous solution (50mL) cancellation also extracts with EtOAc (50mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 7%MeOH/EtOAc gradient elution) and purification thus obtain title compound (0.070g, 82%). 1h NMR (400MHz, CDCl 3) δ 10.42 (s, 1H, br), 8.74 (dd, J=8.4,1.6Hz, 1H), 8.54 (dd, J=4.8,1.6Hz, 1H), 7.64 (s, 1H), 7.40 (dd, J=6.8,4.6Hz, 2H), 7.23 (m, 1H), 7.18 (dd, J=8.6Hz, 2H), 6.94 (s, 1H, br), 5.94 (dd, J=9.2,9.2Hz, 1H), 3.94 (m, 3H), 3.07 (septet, J=6.8,1H), 2.75 – 2.95 (m, 2H), 1.33 (d, J=7.6Hz, 3H), 1.28 (d, J=7.2Hz, 3H); MS:(ES) m/z calculates C 25h 23fN 8o [M+H] +471.2, actual measurement 471.2.
Embodiment 34
The synthesis of 3-[the chloro-3-of 4-(1-hydroxyl-1-Methylethyl)-5-methyl pyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one and 3-[the chloro-5-of 4-(1-hydroxyl-1-Methylethyl)-3-methyl pyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one
The bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.045g in DMF (1.5mL) is stirred at 60 DEG C, 0.20mmol), 2-(4-chloro-5-methyl isophthalic acid H-pyrazole-3-yl) different propan-2-ol (0.070g, 0.40mmol) and K 2cO 3the mixture of (0.05g, 0.40mmol) 1 hour.Then cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtains two pure fractions.Corresponding 3-[the chloro-3-of 4-(1-hydroxyl-1-Methylethyl)-5-methylpyrazole-1-base]-1-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.012g, 13%) of first fraction.Corresponding 3-[the chloro-5-of 4-(1-hydroxyl-1-Methylethyl)-3-methylpyrazole-1-base]-1-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.012g, 13%) of second fraction.1H NMR (400MHz, the CDCl of 3-[the chloro-3-of 4-(1-hydroxyl-1-Methylethyl)-5-methylpyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one 3): δ 7.59 (s, 1H), 7.38 (dd, J=9.0,4.8Hz, 2H), 7.19 (dd, J=8.4,8.4Hz, 2H), 5.02 (dd, J=9.6,7.2Hz, 1H), 4.68 (s, 1H, br), 3.98 (m, 1H), 3.82 (m, 1H), 2.97 (septet, J=7.0Hz, 1H), 2.85 (m, 1H), 2.72 (m, 1H), 2.35 (s, 3H), 1.59 (d, J=8.4Hz, 6H), 1.24 (d, J=7.2Hz, 3H), 1.16 (d, J=7.2Hz, 3H); 3-[the chloro-5-of 4-(1-hydroxyl-1-Methylethyl)-3-methylpyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one 1h NMR (400MHz, CDCl 3): δ 7.54 (s, 1H), 7.36 (dd, J=8.8,4.4Hz, 2H), 7.17 (dd, J=8.6,8.6Hz, 2H), 6.13 (m, 1H), 4.08 (m, 1H), 3.76 (m, 1H), 3.16 (m, 1H), 2.91 (septet, J=7.0Hz, 1H), 2.88 (s,! H, br), 2.65 (m, 1H), 2.18 (s, 3H), 1.79 (s, 3H), 1.62 (s, 3H), 1.14 (d, J=6.8Hz, 3H), 1.03 (d, J=7.2Hz, 3H); MS (two compounds are equivalent): (ES) m/z calculates C 23h 27clFN 5o 2[M+H] +460.2, actual measurement 460.2.
Embodiment 35
The synthesis of 1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-3-[4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
The bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropyl-pyrazoles-4-base] pyrrolidin-2-one (0.020g in DMF (0.6mL) is stirred at 60 DEG C, 0.055mmol), 4-(trifluoromethyl)-1H-imidazoles (0.024g, 0.17mmol) and K 2cO 3the mixture of (0.030g, 0.22mmol) 1 hour.Then by mixture cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtains title compound (0.022g, tfa salt, 75%); 1h NMR (tfa salt) (400MHz, CDCl 3) δ 7.98 (s, 1H), 7.59 (s, 1H), 7.51 (s, 1H), 7.39 (dd, J=8.4,4.8Hz, 2H), 7.20 (dd, J=8.6,8.6Hz, 2H), 5.06 (dd, J=10.8,8.8Hz, 1H), 3.90 (m, 1H), 3.83 (m, 1H), 2.98 (m, 2H), 2.54 (m, 1H), 1.21 (d, J=7.2Hz, 3H), 1.20 (d, J=7.2Hz, 3H); MS:(ES) m/z calculates C 20h 19f 4n 5o (free form) [M+H] +422.1, actual measurement 422.1.
Embodiment 36
The synthesis of 3-[the chloro-3-of 4-(1H-imidazoles-2-base)-5-methylpyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one
A) the bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.055g, 0.15mmol) in DMF (1.5mL) is stirred at 60 DEG C, (0.055g, 0.23mmol) and K 2cO 3the mixture of (0.042g, 0.30mmol) 1 hour.Then by mixture cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 100%EtOAc/CH 2cl 2gradient elution) purification thus obtain 3-(the iodo-5-methylpyrazole of the chloro-3-of 4--1-base)-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.057g, 72%).
B) in a nitrogen atmosphere, 3-(the iodo-5-methylpyrazole of the chloro-3-of 4--1-base)-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.057g, 0.11mmol), Zn (CN) in 85 DEG C of heating DMF (2mL) 2(0.025g, 0.21mmol), Pd 2(dba) 3the mixture of (0.010g, 0.011mmol) and dppf (0.009g, 0.016mmol) 1 hour.Then by mixture cool to room temperature, saturated NaHCO is used 3(30mL) cancellation is also with EtOAc (50mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 100%EtOAc/CH 2cl 2gradient elution) purification thus obtain the chloro-1-of 4-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-2-oxo-pyrroli-3-base]-5-methylpyrazole-3-formonitrile HCN (0.042g, 92%).
C) ethane-1 is stirred at 100 DEG C, the mixture of the chloro-1-of 4-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-2-oxo-pyrroli-3-base]-5-methylpyrazole-3-formonitrile HCN (0.042g, 0.10mmol), HOAc (0.23mL) and EtOH (1.25mL) in 2-diamidogen (1.5mL) 2.5 hours.Then by mixture cool to room temperature, saturated NaHCO is used 3aqueous solution (50mL) cancellation also extracts with EtOAc (100mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration thus obtain 3-[the chloro-3-(4 of 4-, 5-dihydro-1H-imidazoles-2-base)-5-methylpyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.041g, 87%).
D) 3-[the chloro-3-(4 of 4-in DMSO (2.0mL) is stirred at 80 DEG C, 5-dihydro-1H-imidazoles-2-base)-5-methylpyrazole-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.041g, 0.087mmol) and the mixture 1.5 hours of Dai Si-Martin's oxidant (0.150g, 0.35mmol).Then by mixture cool to room temperature, saturated NaHCO is used 3aqueous solution (50mL) cancellation also extracts with EtOAc (50mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through reversed-phase HPLC (C18 post, containing the second nitrile – water of 0.1%TFA, as eluent) purification thus obtains title compound (0.025g, tfa salt, 50%). 1h NMR (tfa salt) (400MHz, CDCl 3) δ 7.62 (s, 1H), 7.35 (dd, J=8.4,4.8Hz, 2H), 7.16 (m, 4H), 5.15 (dd, J=8.6,8.6Hz, 1H), 4.02 (m, 1H), 3.82 (m, 1H), 3.05 (m, 1H), 2.97 (septets, J=7.0Hz, 1H), 2.35 (s, 3H), 2.70 (m, 1H), 1.18 (d, J=6.8Hz, 3H), 1.14 (d, J=6.8Hz, 3H); MS:(ES) m/z calculates C 23h 23clFN 7o (free form) [M+H] +468.1, actual measurement 468.1.
Embodiment 37
The synthesis of 3-[4-amino-3-(1H-imidazoles-2-base) pyrazolo [3,4-d] pyrimidine-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one
A) the bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.055g in DMF (2.0mL) is stirred at 60 DEG C, 0.15mmol), 4-amino-1H-pyrazolo [3,4-d] pyrimidine-3-formonitrile HCN (0.050g, 0.31mmol) and K 2cO 3the mixture of (0.050g, 0.36mmol) 1 hour.Then by mixture cool to room temperature, IPA:CHCl is used with water (30mL) cancellation 3(1:2v/v, 100mL) extracts.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 20 ~ 10%MeOH/EtOAc gradient elution) purification thus obtain 4-amino-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-2-oxo-pyrroli-3-base] pyrazolo [3,4-d] pyrimidine-3-formonitrile HCN (0.055g, 82%).
B) ethane-1 is stirred at 100 DEG C, 4-amino-1-[1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-2-oxo-pyrroli-3-base] pyrazolo [3 in 2-diamidogen (1.5mL), HOAc (0.23mL) and EtOH (2.0mL), 4-d] mixture 45 minutes of pyrimidine-3-formonitrile HCN (0.055g, 0.12mmol).Then by mixture cool to room temperature, saturated NaHCO is used 3aqueous solution (50mL) cancellation also uses IPA:CHCl 3(1:2v/v, 100mL) extracts.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration thus obtain 3-[4-amino-3-(4,5-dihydro-1H-imidazoles-2-base) pyrazolo [3,4-d] pyrimidine-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.057g, 97%).
C) 3-[4-amino-3-(4 in DMSO (3mL) is stirred at 80 DEG C, 5-dihydro-1H-imidazoles-2-base) pyrazolo [3,4-d] pyrimidine-1-base]-1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.057g, 0.12mmol) and the mixture 45 minutes of Dai Si-Martin's oxidant (0.100g, 0.23mmol).Then by mixture cool to room temperature, saturated NaHCO is used 3aqueous solution (50mL) cancellation also extracts with EtOAc (50mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through reversed-phase HPLC (C18 post, containing the second nitrile – water of 0.1%TFA, as eluent) purification thus obtains title compound (0.035g, tfa salt, 48%). 1h NMR (tfa salt) (400MHz, CDCl 3) δ 11.96 (s, 1H), 11.12 (s, 1H), 8.17 (s, 1H), 7.65 (s, 1H), 7.40 (dd, J=8.8,4.4Hz, 2H), 7.20 (dd, J=8.6,8.6Hz, 1H), 7.05 (s, 2H, br), 5.74 (dd, J=9.2,9.2Hz, 1H) 3.94 (dd, J=8.4,4.4Hz, 2H), 3.05 (m, 1H), 3.07 (septet, J=7.0Hz, 1H), 2.87 (m, 2H), 1.31 (d, J=6.8Hz, 3H), 1.27 (d, J=6.8Hz, 3H); MS:(ES) m/z calculates C 24h 23fN 10o (free form) [M+H] +487.2, actual measurement 487.2.
Embodiment 38
The synthesis of 1-[1-(4-fluorophenyl)-5-isopropylpyrazol-4-base]-3-[3-(trifluoromethyl) pyrazol-1-yl] pyrrolidin-2-one
The bromo-1-of 3-[1-(4-the fluorophenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.015g in DMF (0.5mL) is stirred at 60 DEG C, 0.041mmol), 5-(trifluoromethyl)-1H-pyrazoles (0.030g, 0.22mmol) and K 2cO 3the mixture of (0.030g, 0.22mmol) 40 minutes.Then by mixture cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction, by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtain title compound (0.014g, 81%). 1h NMR (400MHz, CDCl 3) δ 7.70 (d, J=1.6Hz, 1H), 7.57 (s, 1H), 7.38 (dd, J=8.8,4.8Hz, 2H), 7.18 (dd, J=8.4,8.4Hz, 2H), 6.58 (d, J=2.4Hz, 1H), 5.07 (dd, J=8.8,7.2Hz, 1H), 4.03 (m, 1H), 3.82 (m, 1H), 2.97 (septet, J=7.6Hz, 1H), 2.84 (m, 2H), 1.20 (d, J=7.2Hz, 3H), 1.12 (d, J=7.2Hz, 3H); MS:(ES) m/z calculates C 20h 19f 4n 5o [M+H] +422.1, actual measurement 422.1.
Embodiment 39
The synthesis of 3-[the chloro-5-methyl of 4--3-(trifluoromethyl) pyrazol-1-yl]-1-[1-(4-chlorphenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one
The bromo-1-of 3-[1-(4-the chlorphenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.035g in DMF (0.8mL) is stirred at 60 DEG C, 0.095mmol), the chloro-3-methyl of 4--5-(trifluoromethyl)-1H-pyrazoles (0.050g, 0.27mmol) and K 2cO 3the mixture of (0.050g, 0.36mmol) 40 minutes.Then by mixture cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction, by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtain title compound (0.036g, 78%). 1h NMR (400MHz, CDCl 3) δ 7.57 (s, 1H), 7.47 (m, 2H), 7.34 (m, 2H), 5.05 (dd, J=9.2,6.0Hz, 1H), 4.04 (m, 1H), 3.81 (m, 1H), 2.99 (septets, J=6.8Hz, 1H), 2.87 (m, 1H), 2.76 (m, 1H), 2.42 (s, 3H), 1.22 (d, J=7.2Hz, 3H), 1.12 (d, J=7.2Hz, 3H); MS:(ES) m/z calculates C 21h 20cl 2f 3n 5o [M+H] +486.1, actual measurement 486.1.
Embodiment 40
The synthesis of 1-[1-(4-chlorphenyl)-5-isopropylpyrazol-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
The bromo-1-of 3-[1-(4-the chlorphenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.110g in DMF (1.8mL) is stirred at 65 DEG C, 0.29mmol), 2-methyl-4-(trifluoromethyl)-1H-imidazoles (0.080g, 0.53mmol) and K 2cO 3the mixture of (0.080g, 0.58mmol) 2 hours.Then by mixture cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction, by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtain title compound (0.035g, tfa salt, 21%). 1h NMR (tfa salt) (400MHz, CDCl 3) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.27 (s, 1H), 5.03 (dd, J=10.4,8.8Hz, 1H), 3.89 (m, 1H), 3.81 (m, 1H), 3.04 (septet, J=6.8Hz, 1H), 2.88 (m, 1H), 2.58 (s, 3H), 2.40 (m, 1H), 1.23 (m, 6H); MS:(ES) m/z calculates C 21h 21clF 3n 5o [M+H] +452.1, actual measurement 452.1.
Embodiment 41
The synthesis of 1-[1-(4-chlorphenyl)-5-isopropylpyrazol-4-base]-3-[2-ethyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) 3,3-bis-bromo-1,1,1-trifluoros-propyl-2-ketone (5.40g, 20mmol) and the mixture of sodium acetate trihydrate (5.44g, 40mmol) in water (40mL) reflux 30 minutes, then cool to room temperature.By propionic aldehyde (1.04g, 18mmol) and dense ammonium hydroxide (1.2mL), the solution in MeOH (100mL) slowly joins said mixture.The mixture that stirring at room temperature obtains 3 days, then vacuum concentrated mixture use IPA:CHCl 3(1:2v/v, 200mL) extracts.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 ~ 6%MeOH/EtOAc and 0 ~ 0.6%NH 4oH gradient elution) purification thus obtain 2-ethyl-4-(trifluoromethyl)-1H-imidazoles (0.070g, 2.3%).
B) the bromo-1-of 3-[1-(4-the chlorphenyl)-5-isopropylpyrazol-4-base] pyrrolidin-2-one (0.200g in DMF (1.5mL) is stirred at 65 DEG C, 0.52mmol), 2-ethyl-4-(trifluoromethyl)-1H-imidazoles (0.060g, 0.36mmol) and K 2cO 3the mixture of (0.080g, 0.58mmol) 1.5 hours.Then by mixture cool to room temperature, with water (30mL) cancellation also with EtOAc (50mL) extraction, and by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification thus obtain title compound (0.0022g, tfa salt, 1.0%). 1h NMR (tfa salt) (400MHz, CDCl 3) δ 7.58 (s, 1H), 7.49 (m, 2H), 7.35 (m, 2H), 7.21 (s, 1H), 5.03 (dd, J=10.4,8.8Hz, 1H), 3.88 (m, 1H), 3.81 (m, 1H), 3.03 (septet, J=7.0Hz, 1H), 2.88 (m, 2H), 2.30 (m, 2H), 1.40 (t, J=7.4Hz, 3H), 1.23 (m, 6H); MS:(ES) m/z calculates C 22h 23clF 3n 5o [M+H] +466.1, actual measurement 466.1.
Embodiment 42
(S) synthesis of-1-(1-(4-chlorphenyl)-5-isopropyl-1H-pyrazoles-4-base)-3-(2-methyl-4-(trifluoromethyl)-1H-imidazoles-1-base) pyrrolidin-2-one and (R)-1-(1-(4-chlorphenyl)-5-isopropyl-1H-pyrazoles-4-base)-3-(2-methyl-4-(trifluoromethyl)-1H-imidazoles-1-base) pyrrolidin-2-one
A) in the solution of the α in acetonitrile (60mL)-bromo-gamma-valerolactone (19.8g, 120mmol) and 2-methyl-4-(trifluoromethyl)-1H-imidazoles (4.50g, 30mmol), K is added 3pO 4(19.1g, 90mmol).Serosity is heated to 80 DEG C 2 days, then cool to room temperature, with EtOAc (200mL) dilution, concentrated by diatomite filtration.By flash chromatography (SiO 2, 0 – 3.5% methanol/CH 2cl 2) purification residues thus obtain product, be pasty state colorless solid.
B) lactone intermediate (700mg, 5.1mmol) obtained at 80 DEG C of whipping step a and the mixture of (S)-phenylethanol amine (1.09g, 4.64mmol) 18 hours, cool to room temperature, by flash chromatography (SiO 2, 0.5-2% methanol/EtOAc) and purification thus obtain two diastereo-isomerism products is colourless foam.With diastereo-isomerism ratio (diastereomeric ratio) 99:1 ( 1h NMR) obtain the first eluting isomer (310mg) and with diastereo-isomerism ratio 11:1 ( 1h NMR) obtain the second eluting isomer (200mg).Each diastereomer independently carries out step c and d.
C) in the mixture of the product (186mg, 0.5mmol) of the step b acquisition in dioxane (2mL), 6M H is added 2sO 4(1.25mL, 7.5mmol).The serosity obtained 80 DEG C of heating 1 hour, cool to room temperature also passes through reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification, neutralize the lactone tfa salt thus acquisition colorless solid (53mg that obtain, 0.23mmol), do not need to be further purified and used.
D) room temperature adopts AlMe 3(2M solution, in toluene, 210 μ L, 0.42mmol) process 1, the mixture of the interior ester products that the step c in 2-dichloroethanes (1mL) obtains and 1-(4-chlorphenyl)-5-isopropyl-1H-pyrazoles-4-amine (50mg, 0.21mmol) 30 minutes.Adopt saturated NH 4cl (5mL) cancellation is reacted and is used EtOAc (3 × 3mL) to extract.Dry organic layer over magnesium sulfate, filters, concentrates and pass through flash chromatography (SiO 2, 0 – 100%EtOAc/CH 2cl 2) purification thus obtain required product (50mg, 0.1mmol, 50% productive rate).
E) room temperature adopts Et 3n (40 μ L, 0.29mmol) and mesyl chloride (20 μ L, 0.23mmol) process the product (50mg, 0.1mmol) 30 minutes of the steps d in dichloromethane (0.5mL).Then use 1,2-dichloroethanes (1mL) dilution mixture thing and wash with water (1mL).Dry organic layer filtering over sodium sulfate.In filtrate, add triethylamine (100 μ L, 0.7mmol), then stir the mixture 90 minutes at 65 DEG C, concentrate and pass through reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification.Neutralizing the tfa salt thus acquisition title compound (19mg, 0.041mmol) that obtain, is white solid. 1h NMR (400MHz, CDCl 3) δ 7.55 (s, 1H), 7.48 (d, J=8.6,2H), 7.36 (d, J=8.6,2H), 7.22 (d, J=0.8Hz, 1H), 5.07 (dd, J=10.5,8.9Hz, 1H), 3.91-3.77 (m, 2H), 3.05 (septet, J=7.0Hz, 1H), 2.90-2.82 (m, 1H), 2.52 (s, 3H), 2.42 – 2.31 (m, 1H), (1.24 d, J=3.2Hz, 3H), (1.23 d, J=3.2Hz, 3H); MS:(ES) m/z calculates C 21h 22clF 3n 5o [M+H] +452.1, actual measurement 451.9.Title compound (Regis Cell cat#784104,25cm x 4.6mm, 5 microns are analyzed by chirality normal-phase chromatography; Eluent: 0.1% diethylamide/IPA, 0.6ml/min).The retention time of (the S)-enantiomer generated by step b first eluting diastereomer is 6.8min (being separated with 8:1er).The retention time of (the R)-enantiomer generated by step b second eluting diastereomer is 7.3min (being separated with 78:1er).
Embodiment 43
(3S) synthesis of-1-[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one and (3R)-1-[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) in a nitrogen atmosphere to the 4-methyl-3-oxo-pentanoate (1.72g in MeOH (10mL), NaOMe (2.6g is added in cooling solution (0 DEG C) 12mmol), 25wt% solution, in MeOH, 12mmol) with the chloro-benzene (0.5M of 1-nitrine-4-, in MTBE, 20mL, 10mmol).Mixture stirred at room temperature spends the night, and vacuum is removed MTBE thus obtained thick ester.
B) room temperature adds MeOH (5mL) and 5N NaOH (5mL) in thick ester, the reactant mixture that stirring obtains a hour.Vacuum cools aqueous residue, slowly adds 12N HCl aqueous solution until pH is 2, now produce yellow solid after removing MeOH in ice bath.Then collecting by filtration yellow solid be dissolved in EtOAc (50mL).Then vacuum slowly removes EtOAc, and at the end of inciting somebody to action, white free-flowing solid starts to be formed.At this point, use Et 2o (100mL) dilution thus be settled out white crystal further, obtains 1-(4-chlorphenyl)-5-isopropyl-triazole-4-carboxylic acid (830mg, 3.13mmol, 31% productive rate) by collecting by filtration.
C) to 1-(4-the chlorphenyl)-5-isopropyl-triazole-4-carboxylic acid (830mg in dichloromethane (3mL), DMF (50 μ L) is added in the solution (0 DEG C) of cooling 3.13mmol), drip oxalyl chloride (546 μ L, 6.26mmol) subsequently.After 5 minutes, remove ice bath, mixture stirred at room temperature 1 hour.Vacuum removes CH 2cl 2thus obtain 1-(4-chlorphenyl)-5-isopropyl-triazole-4-formyl chloride, be white solid, it does not need to be further purified for next step.
D) Hydrazoic acid,sodium salt (610mg, in 2.5mL water, 9.39mmol) is joined in acetone (7.5mL) solution of 1-(4-chlorphenyl)-5-isopropyl-triazole-4-formyl chloride of cooling (0 DEG C).The mixture that stirring at room temperature obtains 30 minutes, uses CH 2cl 2(100mL) dilute, with water (50mL) and saline (50mL) washing, dry (MgSO 4), vacuum concentration thus obtain thick 1-(4-chlorphenyl)-5-isopropyl-triazole-4-carbonyl azide (777mg), it does not need to be further purified for next step.
E) 100 DEG C of toluene (12mL) solution stirring 1-(4-chlorphenyl)-5-isopropyl-triazole-4-carbonyl azide (777mg, 2.67mmol) 1.5 hours.Then add HCl aqueous solution (8M, 2.5mL), stir the mixture 1 hour at 100 DEG C, cool to room temperature, dilute with EtOAc (75mL).Then slowly saturated sodium bicarbonate aqueous solution is added until pH is 8.Dry (MgSO 4) organic layer, vacuum concentration, uses Et 2o (50mL) processes thus destroys less desirable " urea by-product ", and this by-product is by removing.Vacuum concentrated filtrate thus obtain 1-(4-chlorphenyl)-5-isopropyl-triazole-4-amine (497mg), it does not need to be further purified for next step.
F) at 0 DEG C, to (3S)-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone (460mg, 2.1mmol) with 1-(4-chlorphenyl)-5-isopropyl-triazole-4-amine (497mg, Me is added in 1,2-dichloroethanes (15mL) solution 2.1mmol) 3al (2M, in toluene, 1.6mL, 3.15mmol).Then mixture stirred at room temperature spends the night, then is cooled to 0 DEG C, adopts 2N HCl (3mL) cancellation and uses saturated NaHCO 3aqueous solution (25mL) neutralizes.Add EtOAc (100mL), stir the mixture gently.Collected organic layer also washs with saline (50mL), dry (MgSO 4) and vacuum concentration.By automatic flash chromatography (SiO 2, 25%MeOH, CH 2cl 2in) purification obtains crude product thus obtain (2S)-N-[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl]-4-hydroxyl-2-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] butyramide (274mg, 28% productive rate).
G) in the solution of the dichloromethane (5mL) of (0 DEG C) (2S)-N-[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl]-4-hydroxyl-2-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] butyramide (274mg, 0.583mmol) of cooling, Et is added 3n (162 μ L, 1.17mmol), drips MsCl (60 μ L, 0.728mmol) subsequently.The solution obtained <10 DEG C of stirring 30 minutes, then uses CH 2cl 2(50mL) dilute, use saturated NH 4cl aqueous solution (30mL) washs, dry (MgSO 4), filter and vacuum concentration thus obtain thick [(3S)-4-[[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl] amino]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-the base]-4-oxo-butyl of 350mg] methanesulfonates, for yellow colored foam, it does not need any being further purified for next step.
H) at 70 DEG C with Et 3n (500 μ L, 3.6mmol) process 1, [(3S)-4-[[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl] is amino]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base]-4-oxo-butyl] methanesulfonates (350mg, 0.607mmol) in 2-dichloroethanes (7mL) 3 hours.After cool to room temperature, directly by flash chromatography (SiO 2, EtOAc, CH 2cl 2in) then by preparing reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purified mixture thus obtain (3S)-1-[1-(4-chlorphenyl)-5-isopropyl-triazole-4-yl]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one, for white powder, for tfa salt (135mg, 49% productive rate). 1h NMR (400MHz, methanol-d 4) δ 7.71 (s, 1H), 7.67 (d, 2H, J=8Hz), 7.55 (d, 2H, J=8Hz), 5.51 (t, J=19,9Hz, 1H), 4.11 – 3.90 (m, 2H), 3.18 – 3.02 (m, 1H), 2.92 (dddd, J=12.7,8.6,6.7,1.5Hz, 1H), 2.74 – 2.59 (m, 1H), 2.50 (s, 3H), 1.21 (ddd, J=7.0,2.1,0.6Hz, 6H).; MS:(ES) m/z calculates C 22h 23clF 3n 5o [M+H]+453.9, actual measurement 453.1. analyzes title compound and its enantiomer by chirality normal-phase chromatography.Regis Pirkle Covalent (R, R) Whelk-O1 (catalogue 1-786201-300), 25cm x 4.6mm, 5 microns; Eluent: 100% isopropyl alcohol, 0.6mL/min, 13.2min (R)-isomers and 15.7min (S)-isomers.Prepare R-enantiomer in a similar manner.
Embodiment 44
The synthesis of 1-[1-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) at 0 DEG C, pyridine (20.46mL, 253mmol) is joined the CH of cyclobutylmethyl acyl chlorides and isopropylidene malonate (12.16g, 84.3mmol) 2cl 2(100mL) in solution, mixture stirred at room temperature 1.5 hours.Then add methanol (100mL), the mixture that stirred at reflux obtains 3 hours, cool to room temperature, distribute between HCl aqueous solution (1M, 200mL) and EtOAc (500mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 – 20%EtOAc/ hexanes gradient elution) and purification thus obtain 3-cyclobutyl-3-oxo-propionic acid methyl ester (11.6g, 88% productive rate).
B) mixture 1 hour of 3-cyclobutyl-3-oxo-propionic acid methyl ester (5.8g, 37.2mmol) and DMF dimethyl-acetal (25g, 210mmol) is stirred at 100 DEG C.After cool to room temperature, vacuum concentrated mixture thus obtain oily residue, is directly used in next step.
C) intermediate (~ 37.2mmol), 4-chlorphenyl hydrazine hydrochloride (6.67g, 37.2mmol) and K that the step b stirred in DMF (50mL) at 100 DEG C obtains 2cO 3the mixture of (10.3g, 74.4mmol) 1 hour.After cool to room temperature, to extract with EtOAc (500mL) with HCl aqueous solution dilution mixture thing (200mL).Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration also passes through flash chromatography (SiO 2, 0 – 10%EtOAc/CH 2cl 2gradient elution) purification thus obtain 1-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-carboxylate methyl ester (8.3g, 76% productive rate).
D) MeOH (25mL), THF (25mL) and H is stirred at 80 DEG C 21-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-carboxylate methyl ester (8.3g, 28.5mmol) in O (12mL) and the mixture of lithium hydroxide monohydrate (3.6g, 85.6mmol) 1 hour.After cool to room temperature, with 1M HCl acidified aqueous solution mixture, and extract with EtOAc (400mL).Be separated organic layer, dry on anhydrous sodium sulfate and vacuum concentration thus obtain 1-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-carboxylic acid (6.92g, 87% productive rate).
E) to CH 2cl 2(100mL) oxalyl chloride (3.78mL, 43.4mmol) and DMF (0.06mL) is added in the mixture of 1-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-carboxylic acid (4.0g, 14.4mmol) in.Room temperature is after 2 hours, vacuum concentration reactant mixture, then is dissolved in 40mL acetone, joins 0 DEG C of NaN 3the H of (3.75g, 57.8mmol) 2in O (40mL) solution.Then saline (150mL) and EtOAc (350mL) is added.Be separated organic layer, on anhydrous sodium sulfate dry also vacuum concentration.In 100mL toluene, stir residue 1 hour at 95 DEG C, cool to room temperature, then at 110 DEG C with 150mL6M HCl aqueous solution process 1 hour.After cool to room temperature, use rare NH 4oH alkalizes mixture also with EtOAc (500mL) extraction.Be separated organic layer, dry on anhydrous sodium sulfate, vacuum concentration, by flash chromatography (SiO 2, 0 – 100%EtOAc/CH 2cl 2gradient elution) purification thus obtain 1-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-amine (2.9g, 81% productive rate).
F) room temperature adopts Me 3al (0.32mL, 0.64mmol, 2M/ toluene) process 1,1-(4-chlorphenyl)-5-cyclobutyl-pyrazoles-4-amine (0.080g in 2-dichloroethanes (2mL), 0.32mmol) and the mixture 1.5 hours of 3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone (0.080g, 0.34mmol).Then adopt saturated sodium bicarbonate aqueous solution cancellation reactant mixture and extract with EtOAc (100mL).Be separated organic layer, dry on anhydrous sodium sulfate and vacuum concentration thus obtain required alcohol intermediate.
G) mesyl chloride (0.027mL, 0.35mmol) is adopted to process CH 2cl 2(1.5mL) alcohol intermediate (~ 0.32mmol) that the step f in obtains and Et 30 DEG C of solution of N (0.067mL, 0.48mmol) 10 minutes.Then also extract with EtOAc (500mL) with saturated sodium bicarbonate aqueous solution alkalization mixture.Be separated organic layer, dry on anhydrous sodium sulfate and vacuum concentration thus obtain described methanesulfonates.
H) methanesulfonates (~ 0.032mmol) that the step g stirred in 1,2-dichloroethanes (3mL) at 75 DEG C obtains and Et 3the mixture of N (0.15mL, 1.07mmol) 3 hours.After cool to room temperature, reactant mixture is directly by flash chromatography (SiO 2, 0 – 100%EtOAc/CH 2cl 2), pass through reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification subsequently thus obtain title compound (0.060g, 40% productive rate, free form). 1h NMR (400MHz, CDCl 3) δ 7.57 (s, 1H), δ 7.43 (m, 2H), 7.36 (m, 2H), 7.23 (d, J=1.2Hz, 1H), 4.95 (dd, J=9.2,8.4Hz, 1H), 3.86 (m, 2H), 3.71 (m, 1H), 2.84 (m, 1H), 2.50 (s, 3H), 2.36 (m, 1H), 1.99 (m, 6H); MS:(ES) m/z calculates C 22h 21clF 3n 5o [M+H] +464.1, actual measurement 464.1
Embodiment 45
(3S) synthesis of-1-[1-(the chloro-3-methoxyl group-phenyl of 4-)-5-isopropyl-pyrazoles-4-base]-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] pyrrolidin-2-one
A) mixture 1 day of 4-methyl-3-oxo-pentanoate (1.98g, 13.7mmol) and DMF dimethyl-acetal (1.95g, 16.4mmol) is stirred at 100 DEG C.After cool to room temperature, vacuum concentration reactant mixture thus remove volatile matter, roughage is directly used in next step.
The solution of (2Z)-2-(dimethylamino methene)-4-methyl-3-oxo-pentanoate (assuming that 13.7mmol) that the 4-chloro-3-methoxyphenyl hydrazine hydrochloride (3.0g, 14.4mmol) b) in 100 DEG C of stirrings DMF (15mL) and step a obtains 8 hours.After cool to room temperature, ice (10g) is adopted to process mixture and stir 5 hours.Filtering mixt also washes with water (15mL).Collect solid, dry and be directly used in next step with high-vacuum pump.
The biphasic solution of 1-(the chloro-3-methoxyl group-phenyl of 4-)-5-isopropyl-pyrazoles-4-carboxylate methyl ester (assuming that 13.7mmol) that the step b c) under agitation in 60 DEG C of heating oxolane (20mL) and water (16mL) obtains and lithium hydroxide monohydrate (1.2g, 22.6mmol) 1.5 hours.After cooling, evaporating mixture also with 1N HCl dilution, extracts with EtOAc (2 × 60mL).Dry organic layer over magnesium sulfate, filters and vacuum concentration.Adopting the mixture of chloroform and hexane (1:4) grind thick brown solid thus obtain product (2.83g, 9.60mmol, 70% productive rate), is white solid.
D) in the solution of the dichloromethane (8.0mL) of 1-(the chloro-3-methoxyl group-phenyl of 4-)-5-isopropyl-pyrazoles-4-carboxylate methyl ester (0.8g, 2.71mmol) of step c acquisition, oxalyl chloride (0.27mL) and 5 DMF are added.Stir the mixture 3 hours and vacuum concentration.High vacuum dry roughage a few hours, then use it for next step.
E) in acetone (7mL) solution of methyl 1-(the chloro-3-methoxyl group-phenyl of the 4-)-5-isopropyl-pyrazoles-4-formyl chloride (assuming that 2.71mmol) of steps d acquisition, add water (3mL) solution of Hydrazoic acid,sodium salt (0.50g, 7.7mmol) fast.Room temperature vigorous stirring mixture 1 hour.Add dichloromethane (12mL) and stratum disjunctum.With salt water washing organic layer, dry over sodium sulfate, concentrated do not need to be further purified used.
Toluene (20mL) solution of the acyl azide intermediate (assuming that 2.71mmol) f) obtained at 95 DEG C of heating steps e 30 minutes, adds 1N HCl (5mL) and heats biphase mixtures at 95 DEG C and spend the night.After cooling, adopt sodium hydroxide solution (2N) to process mixture and extract with chloroform (2 × 20mL).The dry organic layer merged, filters and vacuum concentration over magnesium sulfate.By flash chromatography (SiO 2, 5%MeOH/CH 2cl 2) purification of crude material obtains product (504mg, 1.90mmol, 70% productive rate), is light tan solid.
G) under room temperature under nitrogen by trimethyl aluminium (0.16mL, 2M, in toluene, 0.32mmol) join 1-(the chloro-3-methoxyl group-phenyl of 4-)-5-isopropyl-pyrazoles-4-amine (57mg, 0.21mmol) with (3R)-3-[2-methyl-4-(trifluoromethyl) imidazoles-1-base] oxolane-2-ketone (50mg, in 1,2-dichloroethanes (2mL) solution 0.21mmol).Stir the mixture 30 minutes.By adding several careful cancellation reactions of 1N HCl.After bubbling is calmed down, more 1N HCl are adopted to dilute viscous mixture and use CH 2cl 2(2 × 20mL) extracts.The dry organic extract merged, filters and vacuum concentration over magnesium sulfate.Roughage does not need to be further purified for next step.
H) to thick alcohol intermediate (assuming that 0.21mmol) and the triethylamine (0.10mL of step g acquisition, mesyl chloride (0.025mL, 0.32mmol) is slowly added in dichloromethane (3mL) solution 0.63mmol).Stirring at room temperature reactant mixture 15 minutes, then washes with water with dchloromethane.Be separated organic layer, dry over magnesium sulfate, filter and vacuum concentration.Roughage does not need to be further purified for next step.
I) in the thick mesylate intermediate (assuming that 0.21mmol) of the step h acquisition in 1,2-dichloroethanes (2mL), triethylamine (0.059mL, 0.42mmol) is added.After stirring 2 hours at 60 DEG C, react by adding saturated sodium bicarbonate aqueous solution cancellation and use CH 2cl 2(2 × 20mL) extracts.Merge organic layer.Dry over magnesium sulfate, filter and vacuum concentration.Obtaining title compound (20mg, 0.042mmol, 20% productive rate, through 3 steps) by reversed-phase HPLC (C18 post, containing the Yi Jing – water of 0.1%TFA, as eluent) purification of crude residue, is white solid. 1h NMR (400MHz, CDCl 3) δ 7.63 (d, J=0.6Hz, 1H), 7.49 (d, J=8.3Hz, 1H), 7.29 (s, 1H), 7.02-6.90 (m, 2H), 5.06 (dd, J=9.1,6.0Hz, 1H), 3.98-3.79 (m, 5H), 3.08 (dt, J=14.1,7.4Hz, 1H), 2.93 (dt, J=14.3,7.5Hz, 1H), 2.63 (s, 3H), 2.47 – 2.35 (m, 1H), 1.25 (dd, J=7.1,2.7Hz, 6H); MS:(ES) m/z calculates C 22h 23clF 3n 5o 2[M+H] +482.1, actual measurement 481.9.
Embodiment 46
The present embodiment illustrates the bioactive evaluation relevant to the interested compound of the present invention.
materials and methods
A. cell
1. cCR1 express cell
A) THP-1 cell
THP-1 cell is available from ATCC (TIB-202), suspension culture is in RPMI-1640 culture fluid, and it adds 2mM L-glutaminate, 1.5g/L sodium bicarbonate, 4.5g/L glucose, 10mM HEPES, 1mM Sodium Pyruvate, 0.05%2-mercaptoethanol and 10%FBS.Cell is at 5%CO 2grow under/95% air, 100% humidity and 37 DEG C of conditions, with 1:5 weekly Secondary Culture (take density as 2x 10 twice 5-2x 10 6cells/ml cultured cell), and at 1x 10 6collecting cell during cells/ml.THP-1 cellular expression CCR1, may be used for CCR1 and combines and function test.
2. chemotaxis is tested
In 96 chemotactic room, hole (nerve probe companies (Neuroprobe); Gaithersburg, the Maryland State) in, use the filter that 5 micron openings Merlon, polyvinylpyrrolidone apply, use chemotactic buffer (Hank ' s balanced salt solution (HBSS) and 1%FBS) implement chemotaxis test.Use CCR1 chemokine ligand (i.e. MIP-1 α, CCL15/ leucotaxin; R & d system company; Minneapolis, the Minnesota State) suppression to the migration mediated by CCR1 of assessing compound mediation.Other chemotactic factors (i.e. SDF-1 α; R & d system company; Minneapolis, the Minnesota State) as Specificity control.Lower room is loaded with 29 microlitre chemotactic factors (i.e. 0.1nM CCL15/ leucotaxin) and not commensurability compound, and upper room comprises 100 in 20 microlitres, 000 THP-1 or mononuclear cell.At 37 DEG C of camera incubata 1-2 hour, adopt and with the direct cell counting in the high power field of 5, every hole or by CyQuant test (molecular phycobiliprotein complexes) (detecting a kind of fluorescent dye method of nucleic acid content and microexamination), the cell quantity of lower room is carried out quantitatively.
B. the qualification of CCR1 inhibitor
One of major function of chemotactic factor is the ability that their mediation chemokine receptor expression cells move as leukocyte.In order to confirm that interested compound not only suppresses CCR1 specific binding and signal transduction (at least as measured by calcium mobilization's algoscopy), but also suppressing the migration of CCR1 mediation, have employed chemotaxis test.THP-1 myelomonocytic leukemia cell (being similar to mononuclear cell), and the mononuclear cell of fresh separated, be used as the target by the chemotaxis of CCR1 chemokine ligand (i.e. MIP-1 α, CCL15/ leucotaxin).Cell is placed in the overhead compartment of micropore migration room, and the interested compound that MIP-1 α (or other potent CCR1 chemokine ligands) and concentration increase is loaded in lower chamber.When there is not inhibitor, cellular response chemotactic factor agonist moves to lower chamber; If compound suppresses CCR1 function, then most cells will remain on upper chamber.For determining that compound of interest is to the affinity of CCR1 and the ability confirming its cell migration suppressing CCR1 to mediate, 1 × 10 in Chemotaxis test -10-1 × 10 -4m compound concentration range measures inhibit activities.In this experiment, the amount of compound is change; And cell number and chemotactic factor agonist concentration remain unchanged.At 37 DEG C of incubation chemotactic chambers after 1-2 hour, by testing (Molecular Probes) (a kind of fluorescent dye method detecting nucleic acid content) labelling with CyQuant, detect with Spectrafluor Plus (Tecan) with passing through, the response cell of lower chamber is carried out quantitatively.The computer program Prism of GraphPad company (San Diego, Ca) is for calculating IC 50value.IC 50value is those compound concentrations needed for cell quantity suppressed 50% of response CCR1 agonist.
1. effect in body
A) rabbit model of arthritis mutilans
Substantially rabbit LPS research is carried out as what describe in the J.Immunol.169 such as Podolin (11): 6435-6444 (2002).LPS (10 nanogram) intra-articular injection process Female New Zealand rabbit (about 2 kilograms) is adopted in two knee.Interested compound, if 1.016 (preparing in 1% methylcellulose) or carrier (1% methylcellulose) are with oral twice of 5ml/kg dose volume (first 2 hours of intraarticular lps injection and intraarticular lps injection after 4 hours).LPS is after 16 hours in injection, and lavation knee, carries out cell counting.Effective effect for the treatment of is determined by the minimizing of the inflammatory cell quantity of raising kneed inflammation synovial fluid.Adopt interested compound to carry out treating the cell causing raising significantly to reduce.
B) in collagen protein induced arthritis rat model, interested compound is evaluated
To induce effect in clinical swollen ankles in arthritis for evaluating interested compound, carrying out the research of 17 days by a definite date II collagen type arthritis.Anti-rat collagen albumen arthritis is the experimental model of polyarthritis, be widely used in the clinical front test of a lot of arthritis reagent (see Trentham etc., J.Exp.Med.146 (3): 857-868 (1977), Bendele etc., Toxicologic Pathol.27:134-142 (1999), Bendele etc., Arthritis Rheum.42:498-506 (1999)).The feature of this pattern is that morbidity is reliable and development is powerful, is easy to the progress detecting multi-joint inflammation, forms relevant remarkable cartilage destruction to pannus, and slightly to bone resorption and the periosteum bone hypertrophy of moderate.
Adopt isoflurane anesthesia Female Lewis rats (about 0.2 kilogram), and inject with back two place bottom tail at the incomplete Freund's adjuvant comprising 2mg/mL cattle II collagen type that adopts for the 0th day and the 6th day of research in these 17 days.From the 0th day until the 17th day uses interested compound with effective dose with subcutaneous way every day.Adopt kind of calliper ankle joint diameter, reduce arthroncus measuring as effect.
The mouse model of dermatosis
Compound of the present invention is assessed in the cutaneous delayed-type anaphylaxis mouse model of Ke azolactone induction.Simply, at the 0th day, the 1% azolactone solution being dissolved in ethanol is adopted to shave a mao abdominal part local sensitization in 8-10 BALB/c mouse in age in week.After sensitization the 6th day, just before the alcoholic solution of auris dextra local application 0.5% azolactone and after 4 hours, the oral the compounds of this invention giving mice carrier or Titration.On next day (the 7th day), slide calliper rule are used to detect ear thickness.Compared with the contrast of vehicle treated, adopt the ear swelling of the animal of compound treatment significantly to reduce, show the skin allergy that compound Jian Qing azolactone is induced
The mouse model of asthma
The compounds of this invention can be evaluated in the mouse model of allergic asthma.By adopting the OVA sensitization 8-10 BALB/c mouse in age in week of adsorbed onto alum adjuvant preparation to induce Mus asthma the 0th day and the 10th day.At the 20th day, the OVA that mice intranasal administration PBS prepares, thus cause airway inflammation.From the 20th day, last till the 23rd day, adopt the compounds of this invention process of carrier or Titration respectively to organize mice.Cellular infiltration thing in the bronchoalveolar lavage (BAL) of the 23rd day analyzing animal after intranasal administration OVA.Relative to the mice of vehicle treated, BAL quantity of leucocyte significantly reduces and shows that compound is effective in the model.
The mouse model of systemic lupus erythematosus (sle)
Present embodiment describes the process evaluated CCR1 antagonist and be used for the treatment of systemic lupus erythematosus (sle) (SLE) effect.Female NZB/W FI mice at 6 months spontaneous beginning develop SLE sample pathology, it is by albuminuria, autoantibodies, glomerulonephritis and final dead characterize.Effect of CCR1 antagonist in following test three serial NZB/W FI mice group (often group comprises 20 mices): the mice of First Series accepts phosphate-buffered salt (PBS) and tween 0.5% with different dosage peritoneal injections soon and afterwards after wean.The mice group of second series after wean soon and afterwards with different dosages by intraperitoneal, intravenous, subcutaneous, intramuscular, oral or accepted the CCR1 antagonist of various dose by any other mode of administration.3rd serial mice group, as positive control, adopts anti-IL-10 antibody treatment with different dosages soon and afterwards after wean.According to final death, nephridial tissue, autoantibodies level and the development of albuminuria monitoring of diseases.
The mouse model of cancer
The present embodiment describes evaluates the process of CCR1 antagonist to treatment malignant tumor effect.Normal mouse strain can transplant the various different mouse tumor system of well-characterized, comprises mouse thymus tumor EL4, its transfection have OVA thus can easily evaluate inoculation OVA after tumour specific antigen response.The CCR1 Antagonist potency of the mice group that three of following test these tumor models any are serial: to a serial mice PBS that peritoneal injection is extra at once and tween 0.5% after tumour transplatation, then with the administration of different dosing timetable.Second series by after tumour transplatation immediately through intraperitoneal, intravenous, subcutaneous, intramuscular, oral or used the CCR1 antagonist of various dose by any other mode of administration, then formed with the mice group of different dosing timetable administration.The mice of the 3rd series, as positive control, by after tumour transplatation immediately intraperitoneal use anti-IL4 antibody, anti-IFNg antibody, IL4 or TNF, then formed with the group of different dosing timetable administration.By tumor growth and the monitoring effect that disappears.In OVA transfection EL4 thymoma model, draining lymph node cells can be stimulated by external use OVA and detect the response of molten cell OVA specificity at 72 hours detectable antigens specific cytotoxics.
Psoriasic mouse model
Present embodiment describes the process evaluating CCR1 antagonist effect in psoriasis.Psoriasis rodent model can be obtained by purified T cell (the being called CD45Rbhi T cell) intravenous available from BALB/c mouse spleen is transferred to immunodeficiency receptor CB.17scid/scid mice.After proceeding to 8 weeks, mice was at the sign of psoriasic rubescent, the swelling of their ear, foot and afterbody appearance those mankind similar and skin injury.Three serial mice groups, comprise and often organize 10-15 CB.17scid/scid mice, inject the CD45Rbhi T cell of purification.In addition, First Series mice receives phosphate-buffered salt (PBS) and tween 0.5% with various dose scheme peritoneal injection when initial cell proceeds to and thereafter.Second series to be included in when initial cell proceeds to and thereafter with various dose scheme by intraperitoneal, intravenous, subcutaneous, intramuscular, oral or accepted the mice group of various dose CCR1 antagonist by any other mode of administration.The mice of the 3rd series, as positive control, is included in when initial cell proceeds to and adopts the antibody of IL-12, IL-4, IFNg or TNF thereafter with various dose scheme or adopt the group of cytokine IL-10 process.For psoriasis sample pathological development monitors animal 3 months after cell proceeds to.
The mouse model of inflammatory bowel
Lack MDR1a-knock-out mice spontaneous formation colitis under specific pathogen free concrete conditions in the establishment of a specific crime of P-glycoprotein gene.In these animals, pathological characteristics has been accredited as the inflammation of Th1 type T cell mediation, similar with people's ulcerative colitis.Disease approximately starts to produce usually after birth in 8-10 week.But disease occur age and final penetrance level often widely different between different animals facility.In the research using MDR1a-knock-out mice, preventative or therapeutic evaluation can be made according to administration time to CCRL antagonist.Interested compound is administered to female mice (n=34) in the mode suitable to compound, and such as every day uses effective dose with subcutaneous way.This research assessment IBD relative growth is slow, and marks for anus ejection and stimulation.Reduce anus ejection and stimulation or suppress the slow compound of IBD relative growth to show the effect of compound in this indication.
The mouse model of entity tumor
Mice RENCA tumor model accurate analog become human renal cell carcinoma progress (especially spontaneous metastasis to lung) and as solid tumor models.Balb/c 6-8 female mice in age in week inoculates about 5e5RENCA cell (Mouse Kidney adenocarcinoma under the scrotum; ATCC cat#CRL-2947), observe tumor of kidney growth through 22 days, observe Lung metastases as far back as the 15th day.When tumor is implanted, give receive vehicle or the compounds of this invention, such as every day subcutaneous administration, thus the impact of monitoring on Primary growth, or use in the time (such as 7 days) after a while, to monitor the effect of compound to transfer.Primary tumor region is measured twice weekly with mechanical slide calliper rule.Through type v=pab2/6 calculates gross tumor volume, and wherein a is longest diameter, and b is the secondary longest diameter vertical with a.The reduction of gross tumor volume or transfer sickness rate shows the effect of compound in this disease.
The mouse model of inflammation
The method of Abdominal inflammation is induced to be well known in the art by introducing 3% thioglycolate salt to peritoneum.After introducing thioglycolate salt, immunocyte pours in site rapidly, mainly with the neutrophil cell of CCR1, causes local inflammation at 24 hours.PE is sampled, can assess cell number and composition to determine before TGA Salt treatment, period or the anti-inflammatory property of compound of interest that gives afterwards.When using in this mensuration, compound 1.042 of the present invention causes total cell and neutrophil cell digital display work to reduce, and shows effectiveness and the coverage biology (biological coverage) of target receptor.
In table 2 (below), provide the structure and activity of representative compound described herein.Activity as follows is provided for the test of above-mentioned chemotaxis :+, 20 μMs of >IC 50>100nM; ++, IC 50<100nM.
Table 2

Claims (28)

1. the compound that represents of structural formula (I), or its any salt, solvate, hydrate, N-oxide or rotamer,
Wherein n is the integer of 0-3;
Each A is independently selected from N or CH;
X and Z is independently selected from lower group separately:
(i) monocycle or fused bicyclic aryl and heteroaryl, wherein heteroaryl have be selected from N, O and S 1-4 hetero atom as ring members;
(ii) be selected from the monocycle four of cycloalkanes or heterocycle alkane-, five-, six-or seven-ring, wherein assorted naphthenic ring have be selected from N, O and S 1-3 hetero atom as ring members;
Each ring wherein in (i) and (ii) is optionally selected from 1-5 the substituent group replacement of lower group: halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-SO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocycle alkane, hetero atom wherein as the ring summit of heteroaryl and assorted naphthenic ring is selected from N, O and S, and wherein substituent alkyl, cycloalkyl, aryl, heteroaryl and heterocycle alkane moiety are further by 1-3 R areplace; And optionally, two substituent groups on adjacent ring summit are connected thus form extra 5-or 6-ring, it is saturated, undersaturated or fragrant and has the ring summit being selected from C, O, N and S;
R 3be selected from lower group: H, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocycle alkane, wherein the hetero atom on the ring summit of heteroaryl and assorted naphthenic ring is selected from N, O and S, and wherein R 3alkyl, cycloalkyl, aryl, heteroaryl and heterocycle alkane moiety be further by 1-3 R areplace;
R 4be selected from lower group: H ,-OR aoptionally by-OR athe C replaced 1-8alkyl;
R 9be selected from lower group: H and optionally by-OR athe C replaced 1-8alkyl;
Each R aand R bindependently be selected from lower group: hydrogen, hydroxyl, halogen, cyano group, C 1-8alkyl, C 1-8alkoxyl, C 1-8haloalkyl, C 3-6cycloalkyl, C 3-6cycloalkyl-alkyl, amino, C 1-8alkyl amino, two C 1-8alkyl amino, carbamyl, carboxyl C 1-4arrcostab, carboxylic acid and-SO 2-C 1-8alkyl.
2. compound as claimed in claim 1, by following representation or its pharmaceutically acceptable salt, hydrate, solvate, rotamer or N-oxide:
Wherein, A 1for N or C (R 5);
A 2for N or C (R 7);
R 5, R 6, R 7and R 8independently be selected from lower group: H separately, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-NR ar b,-CONR ar b, aryl, 5-or 6-unit's heteroaryl and 3-, 4-, 5-or 6-unit heterocycle alkane, wherein the hetero atom on the ring summit of heteroaryl and assorted naphthenic ring is selected from N, O and S, wherein R 5, R 6, R 7and R 8alkyl, cycloalkyl, aryl, heteroaryl and heterocycle alkane moiety be further by 1-3 R areplace; And optionally, R 5, R 6, R 7and R 8neighbor members be connected thus form extra 5-or 6-ring, it is saturated, undersaturated or fragrant and has the ring summit being selected from C, O, N and S.
3. compound as claimed in claim 2, is characterized in that, R 8not H.
4. compound as claimed in claim 2, by following representation:
Wherein,
R 1and R 2independently be selected from lower group: H separately, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-SO 2r a,-NR ar b,-CONR ar bwith 3-, 4-, 5-or 6-unit heterocycle alkane, wherein the hetero atom on the ring summit of assorted naphthenic ring is selected from N, O and S, and wherein R 1and R 2alkyl, cycloalkyl and heterocycle alkane moiety be further by 1-3 R areplace.
5. compound as claimed in claim 4, is characterized in that, each R 1and R 2independently be selected from lower group: H, halogen, CN, C 1-8alkyl, C 1-8haloalkyl ,-CO 2r awith-SO 2r a.
6. compound as claimed in claim 4, is characterized in that, R 9for H or CH 3.
7. compound as claimed in claim 4, by following representation:
Wherein n is 1,2 or 3.
8. compound as claimed in claim 7, it is characterized in that, n is 1.
9. compound as claimed in claim 4, is characterized in that having N, A 1and A 2loop section as ring summit is selected from:
Wherein wave represents the junction point with compound remainder.
10. compound as claimed in claim 4, is characterized in that having N, A 1and A 2loop section as ring summit is selected from:
Wherein,
R 1and R 2independently be selected from lower group: H separately, halogen, CN, C 1-8alkyl, C 3-8cycloalkyl, C 2-8thiazolinyl, C 2-8alkynyl, C 1-8haloalkyl, C 1-8hydroxyalkyl ,-OR a,-CO 2r a,-SO 2r a,-NR ar b,-CONR ar bwith 3-, 4-, 5-or 6-unit heterocycle alkane, wherein the hetero atom on the ring summit of assorted naphthenic ring is selected from N, O and S, and wherein R 1and R 2alkyl, cycloalkyl and heterocycle alkane moiety be further by 1-3 R areplace; With
R 7for H or Cl, R 8for optionally by 1 or 2 R athe C replaced 1-8alkyl; With
Wherein wave represents the junction point with compound remainder.
11. compounds as claimed in claim 8, by following representation:
Wherein R 1for Cl or F.
12. compounds as claimed in claim 11, by following representation:
13. compounds as claimed in claim 11, by following representation:
14. compounds as claimed in claim 11, by following representation:
15. compounds as claimed in claim 8, by following representation:
Wherein R 1for Cl or F.
16. compounds as claimed in claim 8, by following representation:
17. compounds as claimed in claim 8, by following representation:
18. compounds as claimed in claim 8, by following representation:
19. compounds as described in any one of claim 10,11,12,13,16,17 or 18, is characterized in that, R 3be selected from lower group: H, C 1-8alkyl, C 3-8cycloalkyl and C 2-8thiazolinyl.
20. 1 kinds of pharmaceutical compositions, comprise compound according to claim 1 and pharmaceutically acceptable excipient or carrier.
21. 1 kinds of pharmaceutical compositions, comprise compound according to claim 2 and pharmaceutically acceptable excipient or carrier.
Treat the disease of CCR1 mediation or the method for disease, comprise the compound according to claim 2 of the subject effective dose having these needs for 22. 1 kinds.
23. method as claimed in claim 22, is characterized in that, disease or the disease of described CCR1 mediation are inflammatory disease.
24. method as claimed in claim 22, is characterized in that, disease or the disease of described CCR1 mediation are immunoregulatory disorders.
25. methods as claimed in claim 22, it is characterized in that, disease or the disease of described CCR1 mediation are selected from lower group: transplant rejection, dermatitis, eczema, urticaria, vasculitis, inflammatory bowel, food anaphylaxis, asthma, Alzheimer, parkinson disease, psoriasis, lupus erythematosus, apoplexy, restenosis and encephalomyelitis.
26. methods as claimed in claim 22, is characterized in that, disease or the disease of described CCR1 mediation are selected from lower group: rheumatoid arthritis, multiple sclerosis, osteoarthritis, multiple myeloma and osteoporosis.
27. methods as claimed in claim 22, is characterized in that, described in be oral, parenteral, rectum, percutaneous, Sublingual, nose or local give.
28. methods as claimed in claim 22, is characterized in that, described compound is that associating antiinflammatory, analgesic, antiproliferative, metabolic poison, leucocyte migration inhibitor or immunomodulator give.
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